Decision matrix. 1.1 Measuring blood pressure. Summary of evidence from previous surveillance. Summary of new intelligence from 4- year surveillance

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1 Decision matrix Summary of evidence from previous year 1.1 Measuring blood pressure No clinical questions. Recommendations Healthcare professionals taking blood pressure measurements need adequate initial training and periodic review of their performance. [2004] Because automated devices may not measure blood pressure accurately if there is pulse irregularity (for example, due to atrial fibrillation), palpate the radial or brachial pulse before measuring blood pressure. If pulse irregularity is present, measure blood pressure manually using direct auscultation over the brachial artery. [new 2011] Healthcare providers must ensure that devices for measuring blood pressure are properly validated, maintained and regularly recalibrated according to manufacturers instructions. [2004] When measuring blood pressure in the clinic or in the home, standardise the environment and provide a relaxed, temperate setting, with the person quiet and seated, and their arm outstretched and supported. [new 2011] If using an automated blood pressure monitoring device, ensure that the device is validated and an appropriate cuff size for the person s arm is used. [new 2011] Surveillance decision In people with symptoms of postural hypotension (falls or postural dizziness): measure blood pressure with the person either supine or seated. measure blood pressure again with the person standing for at least a minute prior to measurement. [2004, amended 2011] If the systolic blood pressure falls by 20 mmhg or more when the person is standing: review medication measure subsequent blood pressures with the person standing consider referral to specialist care if symptoms of postural hypotension persist. [2004, amended 2011] 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG127 1 of 236

2 year Evidence at the 2-year review was considered to have a possible impact on the guideline. New evidence identified at the 4-year review does not impact current recommendations. No review question this section should not be updated. 2-year (2013) Myers conducted a cluster randomised trial with 88 doctors (67 practices) examining the accuracy of manual blood pressure measurements. Results indicated that in patients with systolic hypertension, introduction of automated office blood pressure into routine primary care significantly reduced the white coat response (phenomenon in which patients exhibit a blood pressure level above the normal range, in a clinical setting, though they don't exhibit it in other settings) compared with the ongoing use of manual office blood pressure measurement. The quality and accuracy of automated office blood pressure in relation to the awake ambulatory blood pressure was also significantly better when compared with manual office blood pressure. Myers et al. (2012) 12 conducted an RCT (n=252) to compare automated office BP (AOBP) or conventional manual office BP (MOBP) measurement for the detection of masked hypertension. Results showed that the prevalence for masked hypertension based on SBP and DBP was 11-15% for AOBP and 19-20% for MOBP patients on single visits, and 4 and 6% when all three visits were used. The authors concluded that the prevalence of masked hypertension is lower with AOBP compared with MOBP. This is unlikely to impact recommendations None identified relevant to this question. New evidence is unlikely to impact on guideline recommendations The following evidence was identified: An RCT 11 investigating the accuracy of manual blood pressure measurements was thought to have a possible impact on the guideline. An RCT 12 comparing automated and manual office blood pressure. This does not impact current recommendations. The evidence update (EU) included this study in section 1.2 but the review (SR) concluded it was more 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG127 2 of 236

3 year relevant to this area. ABPM was used as the gold standard so it was not possible to make the conclusions that the EU made. The new evidence identified at the 2-year review was considered to have a possible impact on the guideline. The SR felt evidence from Myers was more appropriate in this section, as recommendations do not specify whether to use automated or manual devices (although Chapter 9 does specify to use CBPM). Evidence Update (2013) No relevant evidence identified. 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG127 3 of 236

4 year 1.2 Diagnosing of hypertension In adults with suspected primary hypertension, what is the best method to measure blood pressure (HBPM versus ABPM versus CBPM) to predict the development of cardiovascular events? In adults with suspected primary hypertension, what is the best method to measure blood pressure (HBPM versus ABPM versus CBPM) to establish the diagnosis of hypertension? In adults with primary hypertension, what protocol should be used when measuring ambulatory BP for treatment and diagnosis? In adults with primary hypertension, what protocol should be used when measuring BP at home for treatment and diagnosis? If used, should ambulatory or home blood pressure readings be interpreted differently to office measurements? i.e. are different thresholds for intervention/targets for treatment required, or should adjustment be made to readings. Recommendations When considering a diagnosis of hypertension, measure blood pressure in both arms: If the difference in readings between arms is more than 20 mmhg, repeat the measurements. If the difference in readings between arms remains more than 20 mmhg on the second measurement, measure subsequent blood pressure in the arm with the higher reading. [new 2011] If blood pressure measured in the clinic is 140/90mmHg or higher: Take a second measurement during consultation. If the second measurement is substantially different from the first, take a third measurement. Record the lower of the last two measurements as the clinic blood pressure. [new 2011] If the clinic blood pressure is 140/90 mmhg or higher, offer ambulatory blood pressure monitoring (ABPM) to confirm the diagnosis of hypertension. [new 2011] If a person is unable to tolerate ABPM, home blood pressure monitoring (HBPM) is a suitable alternative to confirm the diagnosis of hypertension. [new 2011] If the person has severe hypertension, consider starting antihypertensive drug treatment immediately, without waiting for the results of ABPM or HBPM. [new 2011] While waiting for confirmation of a diagnosis of hypertension, carry out investigations for target organ damage (such as left ventricular 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG127 4 of 236

5 year hypertrophy, chronic kidney disease and hypertensive retinopathy) (see 21) and a formal assessment of cardiovascular risk using a cardiovascular risk assessment tool (see 20). [new 2011] If hypertension is not diagnosed but there is evidence of target organ damage such as left ventricular hypertrophy, albuminuria or proteinuria, consider carrying out investigations for alternative causes of the target organ damage. [new 2011] If hypertension is not diagnosed, measure the person s clinic blood pressure at least every 5 years subsequently, and consider measuring it more frequently if the person s clinic blood pressure is close to 140/90 mmhg. [new 2011] When using ABPM to confirm a diagnosis of hypertension, ensure that at least two measurements per hour are taken during the person s usual waking hours (for example, between 08:00 and 22:00). Use the average value of at least 14 measurements taken during the person s usual waking hours to confirm a diagnosis of hypertension. [new 2011] When using HBPM to confirm a diagnosis of hypertension, ensure that: for each blood pressure recording, two consecutive measurements are taken, at least 1 minute apart and with the person seated and blood pressure is recorded twice daily, ideally in the morning and evening and blood pressure recording continues for at least 4 days, ideally for 7 days. Discard the measurements taken on the first day and use the average value of all the remaining measurements to confirm a diagnosis of hypertension. [new 2011] Refer the person to specialist care the same day if they have: accelerated hypertension, that is, blood pressure usually higher than 180/110 mmhg with signs of papilloedema and/or retinal haemorrhage or suspected phaeochromocytoma (labile or postural hypotension, headache, palpitations, pallor and diaphoresis). [2004, amended 2011] Consider the need for specialist investigations in people with signs and symptoms suggesting a secondary cause of hypertension. [2004, amended 2011] Surveillance decision A small amount of evidence was identified by the 2-year review that could impact the guideline. No new evidence was identified at the 4-year review. This review question should not be updated. 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG127 5 of 236

6 year Evidence Update (2013) Clark et al. (2012) 13 conducted a metaanalysis of 20 cohort or cross-sectional studies of differences in systolic blood pressure between arms in populations of adults of 18 years or older with outcomes of central vascular disease, peripheral vascular disease or death. They found that differences of more than 15mmHg in blood pressure readings between arms may indicate increased or underlying vascular disease. Myers (2011) 11 conducted a cluster randomised trial with 88 doctors (67 practices) examined the accuracy of automated vs. manual blood pressure measurements. The EU took results to indicate that in patients with systolic hypertension, introduction of automated office blood pressure into routine primary care significantly this reduced the white coat response; however the 2-year review has interpreted this evidence differently (see section 1.1). No evidence identified. Topic experts felt that ambulatory monitoring needs clarification, in particular diagnosis and service models for the delivery of ABPM. However, no new evidence in this area has been identified from intelligence gathering. No new evidence was identified at the 4- year review that would affect the review question. However, the new evidence identified at the 2-year review was considered to have a possible impact on recommendation The following evidence was identified: A meta-analysis 13 of 20 cohorts or cross-sectional studies looking at differences in systolic blood pressure between arms. The SR felt this evidence could impact the guideline as it does not support recommendation A cluster randomised trial 11 that does not impact recommendations in this section. The SR felt this study impacted section 1.1 measuring blood pressure. This new evidence identified at the evidence update was considered to support current recommendations (to 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG127 6 of 236

7 year measure blood pressure in both arms and use the arm with the highest blood pressure measurement for all subsequent readings). 2-year (2013) Summarised the Clark 13 study. The review felt this would affect R1.2.1, which states if a difference in readings between arms is more than 20mmHg, the measurements should be repeated. The evidence from Clark suggests this value should be lower, and it was noted that the value given in CG127 may have been from guideline committee consensus. The new evidence identified at the 2-year review was considered to have a possible impact on the guideline. 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG127 7 of 236

8 year 1.3 Assessing cardiovascular risk, target organ damage and secondary causes of hypertension No clinical questions. Recommendations Recommendations cross refer to CG73 and CG67 For NICE guidance on the early identification and management of chronic kidney disease see Chronic kidney disease (NICE clinical guideline 73, 2008) Use a formal estimation of cardiovascular risk to discuss prognosis and healthcare options with people with hypertension, both for raised blood pressure and other modifiable risk factors. [2004] Estimate cardiovascular risk in line with the recommendations on Identification and assessment of CVD risk in Lipid modification (NICE clinical guideline 67). [2008] For all people with hypertension offer to: test for the presence of protein in the urine by sending a urine sample for estimation of the albumin:creatinine ratio and test for haematuria using a reagent strip take a blood sample to measure plasma glucose, electrolytes, creatinine, estimated glomerular filtration rate, serum total cholesterol and HDL cholesterol examine the fundi for the presence of hypertensive retinopathy arrange for a 12-lead electrocardiograph to be performed. [2004, amended 2011] Surveillance decision No evidence was identified by the 2-year review. New evidence was identified at the 4-year review, but this does not impact current recommendations. No review question, this section should not be updated. No relevant evidence identified. Huang et al. (2014) 14 conducted a metaanalysis of 11 cohorts, summarizing the None identified relevant to this question. New evidence is unlikely to impact on guideline recommendations in CG73 and 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG127 8 of 236

9 year risk of cardiovascular disease (CVD) and all-cause mortality (ACM) in relation to alcohol consumption in patients with hypertension, focusing on clarifying doseresponse associations. Compared with the lowest alcohol level (abstainers/occasional drinkers), the pooled relative risk (RR) was 0.72 (95% CI, ) for the third highest category (median, 10 g/d), 0.81 (95% CI, ) for the second highest category (median, 20 g/d), and 0.60 (95% CI, ) for the highest category (median, 30 g/d). A J-shaped relationship between alcohol use and ACM was observed, and the nadir (RR, 0.82; 95% CI, ) was found to be at a dose of 8 to 10 g of alcohol consumption per day. Findings of this meta-analysis suggest that low-to-moderate alcohol consumption was inversely significantly associated with the risk of CVD and ACM in patients with hypertension. This suggests the need to emphasise alcohol consumption in cardiovascular risk assessments, and could impact recommendations. Roush et al. (2015) 15 conducted a systematic review and meta-analysis to determine whether ambulatory blood pressure predicts cardiovascular events in women and men. Whether ambulatory blood pressure (BP) among hypertensive patients better predicts cardiovascular CG67. Evidence suggests the need to emphasise alcohol consumption in cardiovascular risk assessments. This could impact CG127. The following evidence was identified: A meta-analysis 16 of 11 cohort studies looking at the relationship between alcohol consumption and risk of cardiovascular disease and allcause mortality. This study suggested the need to emphasise alcohol consumption in cardiovascular assessments, and could impact recommendations. A meta-analysis 15 looking at whether ambulatory blood pressure in men and women. They found SBP predict higher risks for CVEs in women than in men. This does not affect current recommendations. 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG127 9 of 236

10 year events (CVEs) in women relative to men is unclear (10 cohorts, n = , CVEs = 1892). Analyses showed higher hazard ratios in women than in men from increases in ambulatory but not clinic SBPs. For women relative to men, a 1 SD increase in night-time, daytime, 24 h, and clinic SBP gave hazard ratios (95% confidence limits) of 1.17 ( ), 1.24 ( ), 1.21 ( ), and 0.94 ( ), respectively, whereas a 10 mmhg increase in SBP, gave hazard ratios of 1.06 ( ), 1.13 ( ), 1.10 ( ), and 0.96 ( ), respectively. Authors concluded that in patients with hypertension, increases in ambulatory, but not clinic, SBP predict higher risks for CVEs in women than in men. Although women tended to have greater variability in SBP, this did not entirely explain the sexambulatory BP interactions. This suggests that in patients with hypertension, increases in ambulatory, but not clinic, SBP predict higher risks for CVEs in women than in men. This does not affect current recommendations. 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

11 year 1.4 Lifestyle interventions No clinical questions Recommendations For NICE guidance on the prevention of obesity and cardiovascular disease see Obesity (NICE clinical guideline 43, 2006) and Prevention of cardiovascular disease at population level (NICE public health guidance 25, 2010) Lifestyle advice should be offered initially and then periodically to people undergoing assessment or treatment for hypertension. [2004] Ascertain people s diet and exercise patterns because a healthy diet and regular exercise can reduce blood pressure. Offer appropriate guidance and written or audiovisual materials to promote lifestyle changes. [2004] Relaxation therapies can reduce blood pressure and people may wish to pursue these as part of their treatment. However, routine provision by primary care teams is not currently recommended. [2004] Ascertain people s alcohol consumption and encourage a reduced intake if they drink excessively, because this can reduce blood pressure and has broader health benefits. [2004] Discourage excessive consumption of coffee and other caffeine-rich products Encourage people to keep their dietary sodium intake low, either by reducing or substituting sodium salt, as this can reduce blood pressure.[2004] Do not offer calcium, magnesium or potassium supplements as a method for reducing blood pressure. [2004] Offer advice and help to smokers to stop smoking. [2004] A common aspect of studies for motivating lifestyle change is the use of group working. Inform people about local initiatives by, for example, healthcare teams or patient organisations that provide support and promote healthy lifestyle change. [2004] Surveillance decision The 2-year review did not search for evidence in this area. The 4-year review identified a large amount of evidence, some of which suggest recommendations in this area could be expanded. This section should be updated. 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

12 year No relevant evidence identified. Potassium supplementation (recommendation 1.4.7) Binia et al. (2015) 17 conducted a metaanalysis of 15 RCTs of potassium supplementation in patients not on medication (n=917). They found a reduction of SBP by 6.8 mmhg (95% CI ) and DBP by 4.6 mmhg (95% CI ) in hypertensive patients. Metaregression analysis showed that both increased daily potassium excretion and decreased sodium-to-potassium ratio were associated with blood pressure reduction (P < 0.05). This suggests patients with elevated blood pressure may benefit from increased potassium intake along with controlled or decreased sodium intake, but further studies on the safety of this are required. This study is unlikely to affect current recommendations. Calcium supplementation(recommendation 1.4.7) Cormick et al. (2015) 5 conducted a Cochrane review of calcium supplementation for primary hypertension. They included 16 RCTs (n=3048). They reported evidence to be of high quality and reported various blood pressure outcomes. They concluded calcium intake slightly reduces both systolic and diastolic blood pressure. However, these results should be interpreted with caution, since the proposed biological mechanism explaining Topic experts identified a Cochrane review by Usinger et al. (2012) 4, looking at the effect of fermented milk in hypertension. They found a modest overall effect of fermented milk on SBP was found (MD -2.45; 95% CI to ), and no effect was evident on DBP (MD -0.67; 95% CI -1.48, 0.14). Authors concluded that fermented milk has no clinically important effect on blood pressure, despite the effect found on SBP, as this was very modest. The included studies were very heterogeneous and several with weak methodology. This does not impact the guideline. Other intelligence It should be noted that a cross reference to Cardiovascular disease: risk assessment and reduction, including lipid modification NICE guidelines [CG181] may be needed. New evidence identified that may change current recommendations. Although a large amount of evidence identified supports current recommendations, these recommendations (in particular around lifestyle, diet and relaxation therapies) are unspecific. CG127 did not search for evidence regarding lifestyle interventions. All recommendations came from the 2004 guideline. Here they concluded that there was not enough evidence to accurately identify the long term magnitude of effect that lifestyle interventions could have on hypertension. A large amount of studies have been identified now. Generally these support recommendations or give evidence to suggest lifestyle intervention recommendations could be more specific. This suggests review questions to assess lifestyle interventions could be feasible The following evidence was identified. Topic experts A Cochrane review 4 4-year review Potassium A meta-analysis 17 of RCTs on potassium supplementation. They found patients 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

13 year the relationship between calcium and blood pressure has not been fully confirmed. This study is not likely to affect recommendations as hypertension was an outcome and not the population. Vitamins (no current recommendations) 7 RCTs looked at the effect of vitamin D on hypertension. 4 of these found no significant effect, and these do not impact current recommendations. These trials have varying conclusions. A review of these would be required to determine the impact of vitamin D supplements on hypertension outcomes. Arora et al. (2015) 18 conducted an RCT (n=534) on hypertension patients with low vitamin D status. Patients were randomised to low and high vitamin D intake for 6 months, and neither condition reduced blood pressure significantly, suggesting that vitamin D supplementation in this population is not necessary. Chen et al. (2014) 19 conducted an RCT comparing nifedipine monotherapy to nifedipine combined with vitamin D (n=126). At 6 months, the primary end points, a difference in the fall of 24-h mean blood pressure, between the groups was mmhg (95% CI -11.2; -1.1) for systolic blood pressure (p<0.001) and -4.2 mmhg (95% CI -8.8; -0.3) for diastolic blood pressure (p<0.001). Safety and tolerability were similar among the two groups. Authors concluded vitamin D may benefit from supplements, but further evidence is required. This study is unlikely to affect current recommendations. Calcium A Cochrane review 5 of calcium supplementation. They found calcium to slightly reduce blood pressure, but authors concluded further studies were needed. Hypertension was also the outcome and not the population, so this study is unlikely to affect recommendations. Vitamin D 7 RCTs looked at the effect of vitamin D on hypertension. 4 of these found no significant effect, which does not impact current recommendations. 3 RCTs found a benefit of vitamin D supplements for hypertension, and these could impact the guideline. Nitrate supplementation 1 RCT 26 looked at nitrate supplementation. Evidence was limited, and this study would not impact the guideline. Reducing salt intake 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

14 year supplementation can improve blood pressure in patients with hypertension. Witham et al. (2014) 20 conducted an RCT (n=68) to compare vitamin D3 and matching placebo in patients with hypertension. They found that vitamin D did not reduce 24-hour ambulatory BP (systolic, P=0.33; diastolic, P=0.29) and similar results were found for office BP. This suggests that vitamin D3 did not reduce blood pressure in patients with resistant hypertension. Witham et al. (2013) 21 conducted an RCT (n=159) to compare the effects of cholecalciferol or matching placebo in hypertensive patients. Results showed that there was no treatment effect for any outcomes including office BP, 24 hour BP, arterial stiffness and cholesterol level. This suggests that vitamin D does not improve BP or markers of vascular health systematic reviews and 9 RCTs were identified, most of which support recommendation A Cochrane review found a modest reduction in salt intake could improve outcomes for hypertension patients. Blood pressure in hypertensive patients. The current recommendations to reduce salt intake from 9-12 to 5-6 g/day will have a major effect on blood pressure, but a further reduction to 3 g/day will have a greater effect and should become the long term target for salt intake. This Cochrane review suggests that recommendations on lowering salt intake could be more specific within the hypertension guideline. This may impact the guideline, however it is unclear whether the mean effect of -5.39mmHg is a clinically important effect Currently targets for salt lowering are covered by NICE public health guidance RCTs found a benefit of vitamin D supplements for hypertension, and these could impact the guideline. Larsen et al (2012) 22 conducted an RCT (n=130) comparing daily cholecalciferol supplementation (75 µg [3,000 IU]) for 20 weeks in the winter versus placebo. Compared with placebo, a non-significant 3/1 mm Hg (P = 0.26/0.18) reduction was found in 24-h BP. In patients with vitamin D insufficiency (<32 ng/ml) at baseline, 24- h BP decreased by 4/3 mm Hg (P = A systematic review found that counseling methods on sodium restriction, and found that none of these methods were suitable to be incorporated into UK primary care. This does not impact recommendations 4 RCTs supported current recommendations on salt intake, and 3 RCTs did not impact current recommendations. Specific food diets 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

15 year 0.05/0.01). Central BP (CBP) was reduced by 7/2 mm Hg (P = 0.007/0.15) vs. placebo. The authors concluded that cholecalciferol supplementation, by a dose that effectively increased vitamin D levels, did not reduce 24-h BP, although central systolic BP decreased significantly. In a post-hoc subgroup analysis of 92 subjects with baseline p-25(oh)d levels <32 ng/ml, significant decreases in 24-h systolic and diastolic BP occurred during cholecalciferol supplementation. Forman et al. (2013) 23 conducted an RCT comparing 1000, 2000, or 4000 international units of cholecalciferol per day with placebo for 3 months (n=283 blacks). They found that the difference in systolic pressure between baseline and 3 months was +1.7 mm Hg for those receiving placebo, mm Hg for 1000 U/d, -3.4 mm Hg for 2000 U/d, and -4.0 mm Hg for 4000 U/d of cholecalciferol (- 1.4 mm Hg for each additional 1000 U/d of cholecalciferol; P=0.04). For each 1-ng/mL increase in plasma 25-hydroxyvitamin D, there was a significant 0.2-mm Hg reduction in systolic pressure (P=0.02). There was no effect of cholecalciferol supplementation on diastolic pressure (P=0.37). Authors concluded within an unselected population of black people, 3 months of oral vitamin D3 supplementation significantly, yet modestly, lowered systolic pressure systematic reviews and 1 RCT were identified looking at the effect of garlic on hypertension. The analyses were flawed or limited, more rigorously designed randomized controlled trials focusing on primary endpoints with longterm follow-up are still warranted before garlic can be recommended to treat hypertensive patients. These studies are unlikely to impact the guideline. 1 RCT 39 compared the consumption of whey protein-based beverages with an energy-matched low protein, high carbohydrate beverage. They found no differences between the groups. This study does not impact the guideline 1 RCT 40 looked at dark chocolate consumption in patients, and found it had no impact on blood pressure. This does not impact the guideline. 1 RCT 41 looked at black tea consumption in patients, and found a slight improvement in cardiovascular risks. However this was a small study and is unlikely to impact the guideline. Fat related diets 2 studies investigated the impact of different types of fat intake on hypertension. One study found no significant impacts, and this study is 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

16 year Mozaffari-Khosravi et al. (2015) 24 conducted an RCT (n=42) to compare the effects of a vitamin D supplement and placebo in patients with elevated BP. Results showed that those in the vitamin D group had significant decreases in SBP, DBP and mean arterial BP compared with the placebo group (SBP: -6.4+/-5.3 vs. 0.9+/-3.7mmHg, P<0.001); DBP: -2.4+/-3.7 vs. 1.0+/-2.7mmHg, P=0.003; and MAP: /-3.6 vs. 0.9+/-2.5mmHg, P<0.001). This suggests that vitamin D can aid the control of SBP, DBP and MAP, however this study is small and unlikely to impact current recommendations. Szabo et al. (2012) 25 conducted an RCT (n=2501) to compare the effects of B- vitamins and placebo, n-3 fatty acids and placebo, both B-vitamins and n-3 fatty acids, or placebo alone. They found no effect of supplementation with either B- vitamins or n-3 PUFA. This suggests that B-vitamins and n-3 fatty acids should not be used to reduce BP. This does not impact current recommendations. Other supplement (no current recommendations) unlikely to affect the guideline. One study found a slight improvement of hypertension, but this study is too small to impact the guideline. Protein related diets 1 RCT 44 compared high protein diets to low protein diets in hypertension patients. They found that BP reduction after weight loss is better maintained when intake of protein is increased at the expense of carbohydrates. This supports recommendations to offer lifestyle advice and ascertain people s diet, and suggests dietary recommendations could be more specific. Fruit and vegetables 1 RCT 45 compared high fruit and vegetable consumption with low consumption. Their finding support recommendations to offer lifestyle advice and ascertain people s diet, and suggests dietary recommendations could be more specific. Dairy Kapil et al. (2015) 26 conducted an RCT (n=68) comparing daily dietary nitrate supplementation (250 ml daily, as beetroot juice) with placebo (250 ml daily, as nitrate-free beetroot juice) (n=68; drugnaive (n=34) and treated (n=34) patients 1 meta-analysis 46 looked at the effects of fermented milk on blood pressure. They found it improves outcomes for hypertension patients. This could impact the guideline. 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

17 year with hypertension). They found that daily supplementation with dietary nitrate was associated with reduction in BP measured by 3 different methods. Mean (95% confidence interval) reduction in clinic BP was 7.7/2.4 mm Hg ( / , P<0.001 and P=0.050). Twenty-four-hour ambulatory BP was reduced by 7.7/5.2 mm Hg ( / , P<0.001 for both). Home BP was reduced by 8.1/3.8 mm Hg ( / , P<0.001 and P<0.01) with no evidence of tachyphylaxis over the 4-week intervention period. Authors concluded that these findings suggest a role for dietary nitrate as an affordable, readily-available, adjunctive treatment in the management of patients with hypertension. Further evidence would be required for this to be incorporated into recommendations. Diet (recommendations 1.4.1, 1.4.2, 1.4.6) The 2004 evidence on diet in hypertension was limited, including 14 trials, all of which differed in the type of diet intervention. This review did not identify evidence on diet that would greatly impact current recommendations. Reducing salt intake (recommendation 1.4.6) 2 systematic reviews and 9 RCTs were identified, most of which support recommendation RCTs looked at dairy consumption, and both found a reduction in blood pressure with higher dairy consumption. However these studies were small and unlikely to impact the guideline. Other diet comparisons 2 RCTs looked at other diet comparisons, and both of these support current recommendations to offer lifestyle advice and ascertain people s diet. DASH diet meta-analyses and 4 RCTs 56 looked at the DASH diet in hypertension patients. These all support current recommendations to offer lifestyle advice, but suggests specific diets could be considered and dietary recommendations could be more specific. Exercise meta-analysis and 17 RCTs looked at different exercise interventions in hypertension patients. These all support current recommendations to offer lifestyle advice. However, these studies suggest that recommendations on exercise could specify length or type of treatment (or cross refer to guidelines that have done so). Therapy 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

18 year He et al. (2013) 27 conducted a Cochrane review investigating the effect of modest salt intake reductions on blood pressure. 34 trials (n=3230) were included. Metaanalysis by subgroup showed that in people with hypertension the mean effect was mm Hg (-6.62 to -4.15, I 2 =61%) for systolic blood pressure and mm Hg (-3.54 to -2.11, I 2 =52%) for diastolic blood pressure. In normotensive people, the figures were mm Hg (-3.56 to , I 2 =66%) and mm Hg (-1.85 to , I 2 =66%), respectively. Authors concluded that a modest reduction in salt intake for four or more weeks could cause significant and important falls in blood pressure in hypertensive patients. The current recommendations to reduce salt intake from 9-12 to 5-6 g/day will have a major effect on blood pressure, but a further reduction to 3 g/day will have a greater effect and should become the long term target for salt intake. This Cochrane review suggests that recommendations on lowering salt intake could be more specific within the hypertension guideline. This may impact the guideline, however it is unclear whether the mean effect of mmHg is clinically important. Currently targets for salt lowering are covered by NICE public health guidance 25. Ruzicka et al. (2014) 28 conducted a systematic review (6 RCTs) to evaluate whether efficacious counselling methods 5 RCTs looked at lifestyle modification therapy and other therapies. These support recommendation , but suggest it may be possible for recommendations here to be expanded. They also suggest therapy could be beneficial for hypertension patients, and could impact the guideline; although studies are small and further evidence would be required. Relaxation meta-analysis 10 RCTs looked at different relaxation techniques for hypertension. CG127 does not recommend routine provision of relaxation therapies (1.4.3). However, it does highlight that these can reduce blood pressure. CG127 did not differentiate between types of relaxation therapies. The new evidence identified does not allow comparisons of different types of relaxation therapy. This suggests there is not enough evidence to impact CG127. Additionally, CG127 cross refers to Obesity (CG53) and Prevention of cardiovascular disease at population level (PH25). The cross reference to Obesity needs to be updated (this guideline has been replaced by CG189). 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

19 year on sodium restriction can be successfully incorporated into primary care models for the management of adults with untreated hypertension. Interventions reduced sodium intake (24-h urinary sodium excretion) by 73 to 93 mmol/day (intervention) vs. 3.2 to 12.5 mmol/day (control), paralleled with a reduction in blood pressure (-4 to -27 mmhg) between groups. However, in none of these trials were the 'counselling methods' feasible for application in primary care settings. Apart from multiple sessions of counselling, the interventions were supplemented with provision of prepared food, community cooking classes, and intensive inpatient training sessions. The authors concluded that despite the availability of efficacious counselling methods for the reduction of sodium intake among newly diagnosed hypertensive patients (feasible within a clinical trial setting), none of these methods, in their present form, are suitable for incorporation into existing primary care settings in countries such as Canada, United States, and UK. This does not impact recommendations. Zhao et al (2014) 29 conducted an RCT (n=282 Tibetans aged 40 or older with systolic BP>140 mmhg) comparing three months' supply of salt-substitute (65% sodium chloride, 25% potassium chloride and 10% magnesium sulfate) or control (100% sodium chloride). The net reduction in SBP/DBP in the intervention group 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

20 year versus controls was -7.6/-3.5 mmhg (p<0.05). The proportion of patients with BP under control (SBP/DBP<140 mmhg) was significantly higher in salt-substitute group (19.2% vs. 8.8%, p = 0.027). The authors concluded that low sodium high potassium salt-substitute is effective in lowering both systolic and diastolic blood pressure and offers a simple, low-cost approach for hypertension control among Tibetans in China. This supports current recommendations to reduce salt intake. Zhou et al (2013) 30 conducted an RCT (n=462) comparing the 2-year effects of a reduced-sodium, high-potassium salt substitute (65% sodium chloride, 25% potassium chloride, 10% magnesium sulfate) versus normal salt (100% sodium chloride). For those with hypertension, the mean overall decrease in systolic blood pressure showed a 4-mmHg (95% CI 2-6mmHg, P<0.05) decrease between the two groups. Diastolic blood pressure was not affected by salt use in the hypertensive group. The authors concluded that salt substitution lowers systolic blood pressure in hypertensive patients and lowers both systolic and diastolic blood pressure in normotensive controls. Salt substitution, therefore, may be an effective adjuvant therapy for hypertensive patients and the potential efficacy in preventing hypertension in normotensive individuals. This supports current recommendations to reduce salt intake. 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

21 year Jablonski et al. (2013) 31 conducted an RCT comparing low-sodium condition with normal sodium condition (n=11). They found that urinary marinobufagenin excretion (weekly measurements; /- 1.8 versus /- 2.1 pmol/kg per day), systolic BP (127 +/- 3 versus 138 +/- 5 mmhg), and aortic pulse-wave velocity (700 +/- 40 versus 843 +/- 36 cm/s) were lower during the low- versus normalsodium condition (all P<0.05). Authors concluded that dietary sodium restriction reduces urinary marinobufagenin excretion and that urinary marinobufagenin excretion is positively associated with systolic BP and aortic stiffness (aortic pulse-wave velocity). This supports current recommendations to reduce salt intake. Diaz (2014) 32 conducted an RCT of weight loss and sodium reduction, alone or in combination compared to usual care (n=1820). The trial duration was 36 months. The authors found that in terms of visit to visit variability (VVV) of blood pressure, there was no statistically significant difference between weight loss (7.2±3.1mmHg), sodium reduction (7.1±3.0mmHg) or the combination (6.9±2.9mmHg) compared to usual care (6.9±2.9mmHg). The authors concluded that weight loss and sodium reduction may not be effective for lowering VVV of BP in individuals with high-normal DBP, however it is difficult to conclude as the comparator 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

22 year of usual care is unclear. This does not impact current recommendations. de Almeida Barros et al. (2014) 33 conducted an RCT (n=35) of light salt substitution vs. regular salt in patient with uncontrolled hypertension aged Light salt showed a significant reduction in both SBP and DBP (p<0.05) and in sodium excretion (p=0.016). The regular salt group showed a significant reduction only in SBP. The authors conclude that the light salt substitution for regular salt significantly reduced the BP of hypertensive patients. This supports current recommendations to reduce salt intake. Pinjuh et al (2015) 34 conducted an RCT (n=150 treated hypertensives; initial BP 143.7/84.1 mm Hg in controls and 142.9/84.7 mm Hg in the intervention group) comparing warning labels placed on home salt containers plus a leaflet about the harmful effects of excessive salt intake, versus the leaflet only. After 1 and 2 months, a significant decrease was observed in the intervention group 24-hour urinary sodium excretion (Na24; to 183 +/- 63 mmol and 176 +/- 55 mmol; P <.0001), versus the control group (203 +/- 60 mmol and 200 +/- 58 mmol; P =.1466). A significant drop in BP, by 5.3/2.9 mm Hg, was observed in the intervention group versus controls (0.4/0.9 mm Hg). The authors concluded that significant reduction in Na24 and BP is achieved with 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

23 year warning labels on harmful effects of excessive salt intake. Decreasing daily salt input by 35 mmol may result in an extra BP lowering by some 5-6/2-3 mm Hg. This does not impact recommendations. Allaert et al. (2013) 35 conducted an RCT comparing NaCl monotherapy with NaCl combined with chitosan 3% (Symbiosal) in hypertension patients not on medication. They found that Symbiosal reduced blood pressure more than NaCl monotherapy, for both SBP (P=0.0156) and DBP (P=0.0285). Longer term studies of Symbiosal need to be conducted, looking at outcomes of safety. This study is not likely to affect CG127 recommendations. Specific foods 2 systematic reviews and 1 RCT were identified looking at the effect of garlic on hypertension. Stabler et al. (2012) 36 conducted a Cochrane review and metaanalysis of RCTs looking at the effect of garlic on blood pressure in hypertension patients. 2 RCTs were included. One trial included 47 hypertensive patients, but could not be meta-analysed with the other trial (n=40) as number of patients in each group weren t specified. Authors concluded there is insufficient evidence to determine if garlic provides a therapeutic advantage versus placebo in terms of reducing the risk of mortality and cardiovascular morbidity in patients 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

24 year diagnosed with hypertension. Xiong et al. (2015) 37 conducted a systematic review and meta-analysis to assess the effect of garlic on hypertension. 7 RCTs were included. Compared with the placebo, the meta-analysis revealed a significant lowering effect of garlic on both systolic BP (WMD: mmhg; 95% CI: to -0.99; P = 0.02) and diastolic BP (WMD: mmhg; 95% CI: to ; P < ). No serious adverse events were reported in any of the trials. The present review suggests that garlic is an effective and safe approach for hypertension. However, number of patients included in the analysis was not reported, and more rigorously designed randomized controlled trials focusing on primary endpoints with long-term follow-up are still warranted before garlic can be recommended to treat hypertensive patients. This does not affect current recommendations. Ried et al. (2013) 38 conducted an RCT of 79 hypertensive patients to compare one, two or four garlic extract capsules and placebo. They found that SBP was significantly reduced in the garlic-2- capsule group over 12 weeks compared with placebo (P=0.006), but not significantly different in the 4 capsule or 1 capsule groups compared to placebo. This suggests that garlic extract may be an effective treatment for uncontrolled 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

25 year hypertension, however larger systematic reviews have not found this. This is unlikely to impact the guideline. Hodgson et al. (2012) 39 conducted an RCT comparing daily consumption of whey protein-based beverage (protein) with an energy-matched low-protein highcarbohydrate beverage (control) (n=219). They found no overall differences between groups in blood pressure (P>0.5). Net differences in systolic and diastolic blood pressure were -2.3 (95 % CI -5.3, 0.7) and -1.5 (95 % CI -3.6, 0.6) mmhg at year 1, and 1.6 (95 % CI -1.5, 4.7) and 0.3 (95 % CI -1.9, 2.4) mmhg at year 2. Authors concluded that the present study did not provide evidence that a higher whey protein intake in older women can have prolonged effects on blood pressure. This does not impact the guideline. Koli et al. (2015) 40 conducted an RCT comparing regular consumption of dark chocolate during a reduced snack consumption with reduced the snacks without any added chocolate (n=22). They found that daily consumption of dark chocolate had no effects on 24 h blood pressure, resting blood pressure (mean +/- SD, pre 142 +/- 11.5/89 +/- 8.4 mmhg vs. post 142 +/- 14.2/88 +/- 9.4 mmhg in systolic and diastolic blood pressure, respectively) or arterial stiffness (mean +/- SD, pre / vs. post /- 0.89). Weight was reduced by 1.0 +/ year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

26 year kg during the control (reduced snack only) period, but was unchanged while eating chocolate (p < between the treatments). Authors concluded that inclusion of dark chocolate daily in the diet had no significant effects on blood pressure or other cardiovascular risk factors during a reduced snack period. This does not impact the guideline. Grassi et al. (2015) 41 conducted an RCT comparing black tea (129 mg flavonoids) with placebo twice a day for eight days (n=19). They found that compared to placebo, reflection index and stiffness index decreased after tea consumption (p<0.0001). Fat challenge increased wave reflection, which was counteracted by tea consumption (p<0.0001). Black tea decreased systolic and diastolic BP (-3.2 mmhg, p<0.005 and -2.6 mmhg, p<0.0001; respectively) and prevented BP increase after a fat load (p<0.0001). Authors concluded that regular consumption of black tea may be relevant for cardiovascular protection. This study is too small to impact the guideline on its own. Fat related diets Maki et al. (2013) 42 conducted an RCT comparing low-fat dairy consumption (one serving/day each of 1% fluid milk, low-fat cheese, and low-fat yogurt) with non-dairy products consumption (one serving/day 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

27 year each of apple juice, pretzels, and cereal bar) for 5 weeks (n=62). Dairy and nondairy treatments did not produce significantly different mean systolic blood pressure (SBP) or diastolic blood pressure (DBP) in the resting postprandial state or from pre-meal to 3.5 hours post-meal (SBP, mmhg versus mmhg; DBP, 76.5 mmhg versus 75.7 mmhg), pre-meal (2.35 versus 2.20) or 2 hours post-meal (2.33 versus 2.30) RHI, and premeal (22.5 versus 23.8) or 2 hours postmeal (12.4 versus 13.2) augmentation index. Fasting lipoprotein lipid values were not significantly different between treatments overall, or in subgroup analyses. Authors concluded that no significant effects of consuming low-fat dairy products, compared with low-fat nondairy products, were observed for blood pressures, measures of vascular function, or lipid variables in the overall sample. This does not impact the guideline. Moreno-Luna et al (2012) 43 conducted a crossover RCT (n=24 young women with high-normal BP or stage 1 essential hypertension) comparing a diet with polyphenol-rich olive oil (~30 mg/day), versus one with polyphenol-free olive oil for 2 months each. Compared to baseline values, only the polyphenol-rich olive oil diet led to a significant (P < 0.01) decrease of 7.91 mm Hg in systolic and 6.65 mm Hg of diastolic BP. A similar finding was found for serum asymmetric dimethylarginine (- 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236

28 year / micro mol/l, P < 0.01), oxidized low-density lipoprotein ( / micro g/l, P < 0.01), and plasma C- reactive protein (-1.9 +/- 1.3 mg/l, P < 0.001). The authors concluded that the consumption of a diet containing polyphenol-rich olive oil can decrease BP and improve endothelial function in young women with high-normal BP or stage 1 essential hypertension. This study is too small to impact the guideline. Protein related diets Engberink et al. (2015) 44 conducted an RCT (n=420) of a high protein diet vs. low protein diet in overweight adults, lasting 26 weeks (after an 8 week weight loss period). BP increased in both groups but it was 2.2mmHg less (-4.6 to 0.2) in the high protein group than in the low protein group. The effect was attenuated after adjustment for initial BP and weight change. The authors conclude that BP reduction after weight loss is better maintained when intake of protein is increased at the expense of carbohydrates. This supports recommendations to offer lifestyle advice and ascertain people s diet, and suggests dietary recommendations could be more specific. Fruit and vegetables Macready et al. (2014) 45 conducted an 4-year decision matrix 2016 Hypertension (2011) NICE guideline CG of 236