So what do patients think about hypertension? This systematic review of the literature raised some important points (BMJ 2012;345:e3953):

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1 There is so much we don't know in medicine that could make a difference, and often we focus on the big things, and the little things get forgotten. To highlight some smaller but important issues, we've put together a series of pearls that the Red Whale found at the bottom of the ocean of knowledge! Hypertension Hypertension is not a disease, it is a risk factor for cardiovascular disease (CVD). What is more, unlike age and sex, it is a modifiable risk factor! Why hypertension matters Much of our understanding on hypertension is based on trials that are often decades old. A massive study reviewed contemporary data on hypertension and challenges some of our assumptions. The study looked at 1.25 million people over 30 years of age. None had CVD at the start, although 25% were on antihypertensives (Lancet 2014;383:1899). The study showed the following. There was no J-shaped curve for blood pressure (those with the lowest blood pressures are not at increased risk compared to those with a BP of /60 74). Remember that in Europe many of these individuals are offered treatment for their low blood pressure (to make it higher!). Those who developed hypertension (BP 140/90 or more) developed cardiovascular disease 5y earlier than those without hypertension. The commonest hypertension-related diseases people developed were heart failure and angina. The attributable risk from hypertension varied from one cardiovascular disease to another, and varied whether the systolic or diastolic blood pressure was raised. For example, high systolic blood pressure increased the risk of getting angina and intracranial haemorrhages the most, whereas the risk of developing an abdominal aortic aneurysm was linked much more to diastolic blood pressure, with little impact from systolic blood pressure. Well done! From 1994 to 2011 a cross-sectional study in England has shown that (Lancet 2014;383:1912): Average blood pressures for those with hypertension has fallen from 150/80 to 135/75. Prevalence of those with controlled blood pressure doubled from 33% to 63%. I think primary care should take the credit for this, especially practice nurses! But A survey of 300 GPs found that more than half of GPs in 2015 were not using the correct thresholds to make the diagnosis! Most of these were using higher thresholds and therefore under diagnosing it. In part this was because some were adjusting by 10/5 for home readings (as we used to, but shouldn t any more) (BJGP 2016; DOI: /bjgp16X687037). Time to have a quick check of your protocol and see what it says?? Patients view on hypertension So what do patients think about hypertension? This systematic review of the literature raised some important points (BMJ 2012;345:e3953): Patients think the main causes are stress, food, obesity, family history and alcohol. Stress in particular was identified as a key element: as a cause, as an exacerbator and as a consequence. Many described trying to avoid stress after the diagnosis; avoiding arguments, changing jobs, trying to relax more. Some thought hypertension was a temporary illness that would resolve. Most knew hypertension caused strokes and heart disease. Fewer knew it affected their kidneys. The main symptoms patients associated with hypertension were headaches and dizziness, and most felt the absence of such symptoms showed good disease control. Many had experimented with stopping treatment to see if any symptoms recurred. Lack of symptoms often prompted people to stop medication; presence of symptoms encouraged compliance. Many expressed a fear that long-term medication was harmful because there was a risk of tolerance, dependence or the drug building up to harmful levels. Alternative medicines were widely used and perceived to be more effective. Worth bearing in mind next time you do a medication review for hypertension or talk to a newly diagnosed patient. Poor compliance A BMJ 10 minute consultation suggested if we are finding patients are not taking their antihypertensives we should (BMJ 2016;353:i3268): Explore reasons for not taking medication: ask and listen.

2 Discuss risk (for example using the QRISK took online to show happy/sad faces to look at risks). Discuss the benefits of lifestyle change, which may result in needing less medication. Look at rationalising medications or changing them to reduce side effects. Encourage home monitoring as a way of empowering people to take control. Using motivational interviewing as a way of empowering people to improve adherence. None of this will come as a surprise to you, but I know I am less good at the asking and listening and quick to start telling! BP variability matters! Declaration of interest! One of our team is an author of this paper! We know that mean blood pressure increases CV risk those with a mean clinic reading of 160/100 are at higher risk than those with a mean clinic BP of 130/80. However this meta-analysis looked at variability in blood pressure and its association with cardiovascular risk (BMJ 2016:354:i4098). It isn t the first paper to do this, but the authors tried to get round the short coming in previous papers (e.g. by adjusting for mean BP). BP variability is how much it differs from reading to reading. The study showed that having significant variation in clinic systolic blood pressure increases the risk of: All cause mortality CV mortality CV events. The increased risk was slight (about 1.2 fold). The authors point out it is hard to know exactly what to do with this piece of information in daily practice at present! The accompanying editorial says that (BMJ 2016;354:i4190): Although some studies have shown that certain drugs reduce BP variability more than others (calcium channel blockers are the best), this should not affect our decision about which antihypertensive to use. The study reminds us that risk may be higher than the actual clinic BP suggests if there is significant variation. Risk tools may start to incorporate variability in them but until they do this trial doesn t change our practice. NICE guidelines on hypertension NICE, in conjunction with the British Hypertension Society, published new guidelines on the management of hypertension in 2011 (NICE CG127, August 2011). The key changes were: Ambulatory blood pressure is suggested as the investigation of choice for all with suspected hypertension. Home readings are an alternative, if ambulatory cannot be used. Clinic BP readings are no longer recommended for the diagnosis of hypertension, however, they can (and should) be used to monitor responses to treatment. Why shift to ambulatory monitoring? Because it is better: more robust data are available (looking at CV endpoints) and over-diagnosis rates are lower (home readings over-diagnose 14% of people, clinic readings a whopping 25%). It is also more cost-effective in the long run (in terms of pounds saved and QALYs), as was demonstrated in a modelling study based on typical UK general practice patients (Lancet 2011;378:1219). This included initial investment costs, and the staff costs of clinic vs. home vs. ambulatory monitoring. The threshold blood pressure for offering drug therapy has changed, partly reflecting the move to ambulatory BP monitoring. Diuretics have moved to third line drugs after ACE inhibitors and calcium channel blockers The thiazide-like diuretic of choice is now indapamide rather than bendroflumethiazide or hydrochlorothiazide. The reasons for this are discussed in the FAQs section. However, NICE say that those already established on bendroflumethiazide or hydrochlorothiazide need not be changed to indapamide. These guidelines say they do not apply to those with diabetes, but the subsequent NICE diabetes guidelines (currently draft as we go to press) say that in diabetics hypertension should be managed exactly as it is in everyone else, with the only exception being that ACE inhibitors should be used first line regardless of age. Here I have given you as much detail as I think necessary to understand what NICE has recommended and why. To help you remember this and apply it in the consultation, and to help you develop your own protocol, I have included our own practice s protocol in the Appendix (this is a 2 page summary of the really practical stuff). NICE on hypertension - NICE 2011, CG127 Measure BP using a validated device, with the patient sitting with the arm supported, using an appropriately sized cuff. (A recent study showed that anaeroid machines were most inaccurate, especially those donated by the pharmaceutical industry (56% were inaccurate!) (BJGP 2011;62:564)).

3 If using an automated device check the pulse first: automated devices may not measure BP accurately if the pulse is irregular. If BP is elevated, repeat during the consultation. If the second reading is substantially different from the first, do a third reading. Record the LOWEST reading. NICE suggest measuring blood pressure in both arms initially. If the difference between the 2 arms is >20mmHg, repeat the readings. If this difference persists, all subsequent BP readings should be measured in the arm with the higher readings. We know that very few clinicians actually do this in practice, but we discuss the evidence in the frequently asked questions section! Ambulatory BP readings (ABPM) Use a device that records at least 2 measurements/hour during waking hours. (That means you won t spot the night time non-dippers (those who fail to drop their BP at night), who are at increased CV risk, but NICE do not discuss this probably because we have never managed them differently.) You need to have at least 14 readings to average. In the past we added 10/5 to ABPM before making decisions there is no need to do this now, since the decision flow charts are based on ABPM not clinic readings. Home BP monitoring (HBPM) Take readings morning and evening for at least 4d, preferably 7d. On each occasion take 2 readings 1min apart, whilst seated. Discard the first day s readings, and average the remaining readings. Interpreting ambulatory/home BP readings

4 Drug therapy Aim for drugs to be taken only once daily (a Cochrane review suggested evening dosing might be marginally better in terms of BP control (they didn t look at important CV outcomes), but the DTB suggests this isn t clinically important) (Cochrane 2011 CD004184, DTB 2011;49(12):134). Do NOT use ACE inhibitors and angiotensin receptor antagonists together (no evidence of additional benefit, increased risk of side effects) (a meta-analysis in those with diabetes AND CKD did show combing these two drugs resulted in a reduction in end stage renal disease, but no reduction in mortality, but this can not yet be generalised to other populations) (Lancet 2015;385:2047). Treat women of child-bearing age in line with the NICE guidelines on hypertension in pregnancy (NICE 2010, CG107), summarised in the Pregnancy chapter. Treat isolated systolic BP (SBP 160) in the same way as when both the diastolic and systolic BPs are raised. Do note that NICE now prefer indapamide (2.5mg normal release once daily) to bendroflumethiazide. The reasons for this are discussed in the FAQs section.

5 When to step up therapy/target BPs Monitor response to treatment using clinic BP readings. Only use ambulatory/home readings to monitor response to therapy in those with known white coat hypertension (defined as a discrepancy of >20/10 between clinic and average ambulatory or home readings at time of diagnosis). Increase drug therapy if these targets are not achieved. Aim for: <80y Clinic BP readings of: Ambulatory/home average readings of: <140/90 <135/85

6 80y <150/90 <145/85 Specialist referral Refer same day if: Accelerated hypertension (BP usually >180/110 with signs of papilloedema and/or retinal haemorrhages). Suspected phaeochromocytoma (labile blood pressure with hypertension and postural hypotension, headache, palpitations, pallor and diaphoresis (excessive sweating)). Routine referral: Consider if secondary hypertension suspected. Consider in those aged under 40y with hypertension because they need a more detailed assessment for end organ damage and because 10y CVD risk estimations tend to underestimate risk in these younger individuals. Postural hypotension In those with falls or dizziness on standing, NICE suggest checking lying and standing blood pressures: record BP whilst sitting, and repeat after the patient has been standing for at least 1 minute. NICE suggest a fall in systolic BP of 20mmHg or more should prompt us to: Review medication. Measure subsequent BPs with the person standing. Consider referral if symptoms persist. Frequently asked questions about the NICE guidance Here I will cover: When and how quickly should antihypertensives be added if the BP is raised? Why treat mild hypertension? Treating hypertension based on CVD risk? Why do NICE suggest measuring BP in both arms? Why differentiate initial therapy on race? Which CVD risk assessment tool should we use? Why the change in first line diuretics? What do we do with people already on bendroflumethiazide? Why are diuretics now only third line? Step 4 therapy/resistant hypertension: what next? What role for beta-blockers? How quickly do you get benefit from treatment? Should hypertension be treated differently in obese people? Telemonitoring Long term home monitoring: does it help reduce BP? Hypertension in the elderly What dose of antihypertensives? Drug dilemmas relating to antihypertensives Potato consumption and hypertension When and how quickly should antihypertensives be added if the BP is raised? You see someone with known hypertension, you take their BP and it is up. How quickly do you arrange to re-test their BP or increase their medication? And having increased their medication, when should you follow them up to see if the change has had an effect? A cohort study looked back at the data on people in the UK with a diagnosis of hypertension and who were on at least one anti-hypertensive AND had had at least one step up in therapy AND who had at least 10 years worth of primary care data since diagnosis (BMJ 2015;350:h158). With systolic BP readings above 150, reducing the BP had benefits in terms of cardiovascular outcomes or all cause mortality. However below a systolic of 150, there was little additional benefit from tightening control. The data also suggested that driving BP below a systolic of 130 may be harmful. This is all in line with other emerging evidence. The researchers provided (possibly for the first time) data on the impact of time frames around increasing medication and following up people after a medication increase that is useful: The longer the gap between high readings and adding in a new medication, the greater the cardiovascular risk and the greater the risk of death (from any cause). This is unsurprising, but what sort of time frames make a difference? Those who waited more than 6 weeks between high readings and addition of another drug were at increased risk of cardiovascular events or death.

7 After adding a new drug, if the follow up BP check was more than 2.7 months later this was associated with an increased risk of cardiovascular events or death. The editorial revealed that 60% of the patients waited my than 18 weeks to have their BP medication stepped up and in these patients there was a 20% increased risk of death or CV event (BMJ 2015;350:h167). How quickly do you act on a raised BP reading in someone with hypertension? And how soon after adding a new drug do you check their BP? Why treat mild hypertension? A Cochrane review has recently been published suggesting treatment for mild hypertension may not be beneficial (Cochrane , 2012). The review identified trials of people with a blood pressure in the range of /90 99 without CVD. Almost 9000 people were included. Over 4 5y treatment with antihypertensives: Did not reduce mortality Did not reduce IHD Did not reduce CVA. About 10% of people stopped therapy because of side-effects. NICE currently suggest that we should not offer antihypertensives to those with an ambulatory BP of /85 94 provided they do not have CVD/end-organ damage or a CVD 10 year risk of 20% or more. This Cochrane review supports this stance, and also suggests that people with blood pressures higher than this may not get significant benefit over 4 5y. Longer studies may show benefit (particularly important for younger people). This all adds to the conundrums around hypertension: At what level should we treat? And how many do we have to treat to prevent 1 CV event? And at what cost (patient hassle and worry as well as patient/nhs/society s financial costs)! A BMJ editorial following the publication of this Cochrane review reminds us that this review is important because the authors did not exclude people with risk factors such as diabetes, and probably included people with a 10 year CVD risk of 20% or more (BMJ 2012;345:e5511). However, they also pointed out that most of the patients in the Cochrane review came from a single trial and many were only taking a beta-blocker (for which some argue there is less convincing data around reduction of mortality). Also of note, the total number of events in the trial was relatively small. They also discussed some of the issues this Cochrane review raised: It may be easier to treat than not to treat You never get blamed for over treating as one commentator put it. Benefit from treating severe hypertension is accepted, but the benefit comes from lowering blood pressure just a little. Trying to get everyone to normal blood pressure using multiple drugs may not be beneficial (or achievable) and may actually be harmful. Drug treatment in mild hypertension (and intensive treatment of severe hypertension) may be of greatest benefit to the pharmaceutical industry rather than patients! However a trial of those with or at high risk of CVD (bu t without diabetes) (therefore likely to have a QRISK of 20% or more) found that intensive treatment (aiming for SBP of 120mmHg) was better than standard treatment (aiming for SBP<140). In the target group they achieved a mean SBP of 121mmHg and in the standard arm the mean SBP was 136mmHg) (SPRINT trial, NEJM 2015;373:2103). The trial was stopped early, after just over 3 years because of the benefits from intensive treatment: There were fewer CV events in the intensive treatment arm (MI, CVA, heart failure, death for CVD). NNT 185/year for intensive treatment (that is 185 people need to be treated for 12m with intensive treatment compared to standard treatment to prevent 1 CV event). Side effects (hypotension, syncope, electrolyte abnormalities, acute kidney injury/failure) were significantly more common in the intensive treatment arm (although there was no difference in the number of falls resulting in injury). However it is important to remember this trial was of people with known cardiovascular disease or significant cardiovascular risk factors. How well it applies to those with stage 1 hypertension and no significant cardiovascular risk factors is less clear. A further systematic review (which includes the SPRINT trial among others) of over people (123 studies) showed that, whatever your starting BP was, lowering it reduced CV outcomes (Lancet 2015, doi: /S (15) ). A further meta-analysis of people from trials that randomised people to more and less intensive blood pressure control showed there was benefit from lowering blood pressure including in those who had a starting systolic blood pressure of less than 140. Intensive control resulted in: A reduction in cardiovascular events (MI, CVA) and proteinuria.

8 No reduction in cardiovascular mortality, heart failure or progression to end stage renal disease. The benefits were particularly notable in those with cardiovascular disease, diabetes and renal disease, and the authors suggested it is in those groups we should be encouraged to aim for more intensive control (Lancet 2016;387:435). So what does all this mean in practice? The problem with trials is that they often fail to analyse the data by CV risk. When you look at trials that look at different populations, then a clearer picture emerges: The Cochrane trial, which was mainly people with lower CVD risk, showed no benefit from treatment. Trials such as SPRINT, where many had established CVD, showed benefit from treatment even with stage 1 hypertension. So although these trials make us wonder whether or not the BP curve is J-shaped or not, what might matter more is your CVD risk, rather than your blood pressure itself. This is discussed in more detail in the next section. And of course what we all really want to know is what are the NNTs and NNHs for treating stage 1 hypertension with and without other CV risk factors? A BMJ clinical review suggested, in the light of all this evidence (BMJ 2016;355:i5719): In those with stage 1 hypertension WITHOUT significant cardiovascular risk factors, lifestyle should be first line treatment. In those with significant CV risk factors or established CVD, based on the SPRINT data in particular, drug treatment is warranted. These recommendations are in line with the NICE hypertension guidance. I think this remind us that hypertension is a risk factor, not a disease, and we need to talk to patients with this is mind and perhaps share some of the uncertainties with them and discuss their approach to risk and tablet taking. What we definitely don t want them to think is I ve got high blood pressure, that means I am going to have a stroke, taking these tablets will stop me having that stroke. Because, sadly, it isn t quite that simple Treating hypertension based on CVD risk? This meta-analysis looked at whether we should treat hypertension by stratifying CVD risk first. We do this already to a degree in those with newly diagnosed hypertension we only start drug treatment if the BP is less than 150/90 where the 10y CVD risk is 20% or more. If we were to do this in a more sophisticated way the crucial data we would need would be to establish what benefit is gained by treating people at different starting CVD risks. This meta-analysis did exactly this. The data are based on over patients and include mainly people without CVD (only 8% had CVD) (Lancet 2014;384:591). Do note risks were quoted over FIVE years not ten. Regardless of baseline blood pressure, reducing blood pressure resulted in a reduction in CVD risk (this has been shown in other trials too). The relative risk reduction was similar regardless of baseline risk (around 15%), but the absolute benefit increases with increasing starting risk (see table below). What is more, the absolute benefit increases the more by which the systolic and diastolic blood pressure are reduced (see diagrams below). CV events prevented by baseline CVD risk and systolic BP reduction

9 CV events prevented by baseline CVD risk and diastolic BP reduction Note that the scale for systolic and diastolic reduction are different (systolic 4 16mmHg reduction, diastolic 2 8mmHg reduction). These data allow us to quantify the likely benefits populations will get from certain reductions in blood pressure depending on their baseline CVD risk. Over time we may start to move to a more sophisticated risk-based decision making in hypertension before starting treatment. This would reduce the numbers treated (reducing costs and unnecessary harm) whilst also maximising the number of events prevented. For now though, follow the NICE guidance. Why do NICE suggest measuring BP in both arms? NICE suggests the first time you take someone s blood pressure you should measure it in both arms, and if the difference between the arms is >20mmHg, repeat, and if the difference remains, then all subsequent BP readings should be measured in the arm with the higher readings. A small systematic review and small trial suggested that a 10mmHg inter-arm difference (not 20mmHg as suggested by NICE) might indicate an increased risk of peripheral arterial disease or a weak association with increased CV death (Lancet 2012;379:905, BMJ 2012;344:e1327). A study of over people with a mean age of 62, and an inter-arm blood pressure difference as small as 5mmHg had an increased cardiovascular mortality (HR 1.91, CI 1.2-3). However the study recruited people who had cardiovascular risk factors (as

10 defined as a reduced ankle brachial index) to start of with and the data was based on a SINGLE set of blood pressure readings (BJGP 2016;66:241). Time to wait for some more data we think! Another study looked at the frequency of inter-arm differences, in primary care across a wide range of countries. (BJGP 2016 DOI: /bjgp16X687553). Unfortunately they took 10mmHg as the cut off in difference, whereas NICE says use 20mmHg. They found taking BP in both arms at the same time was more accurate (but totally unpractical, I think, in normal daily practice!). Doing it in one arm after the other increased the risk of getting a significant difference (by 3 fold!). They found inter-arm differences were more common in western than in Asian populations. When you look at the data they give for studies done in UK primary care, a few did report the prevalence of inter-arm difference and the frequency of inter-arm differences was zero at this cut off! The BMJ editorial accompanying the latter paper concluded more work is needed to examine how well between-arm difference compares with other markers of cardiovascular risk (BMJ 2012;344:e2033). In the spring and summer of 2012 we asked several thousand GPs attending our courses (so not a scientifically selected population!) whether they took blood pressure in both arms. Only a handful said yes. I m afraid we are of the view that there are more important things to do in the consultation! Why differentiate initial therapy on race? This is mainly based on sub-group analysis of the ALLHAT trial (one-third of the study population of over were black (of African/Caribbean descent)) which showed that calcium channel blockers were significantly better than ACE inhibitors at reducing the risk of: CV events overall. Stroke. But that CCB and ACE inhibitors were similar in black people at reducing the risk of CHD and heart failure. A recently published study, however, is reassuring they compared actual prescribing in several boroughs with the guideline recommendations (before the new NICE guidance was published) for both black and non-black people (BJGP 2012;62:532). About 44% of patients of each ethnicity were treated in a way that was not in line with NICE guidance(!). However, when they looked at blood pressure control, there was no difference between the groups on the correct or incorrect therapy. This is helpful in that it suggests that the actual order in which we start combinations of therapies may not actually matter in terms of blood pressure control. Of course what we would really like to know is whether being on the correct or incorrect therapy affected CV outcomes, but the study didn t look at this. Which CVD risk assessment tool should we use? This NICE guideline doesn t specify whether QRISK2 or Framingham should be used. However, in the section on CVD risk and lipids (available online), we discuss why the QRISK2 tool is more accurate for the UK population. Why the change in first line diuretics? Thiazide-like diuretics such as indapamide have other properties, not shared with the thiazides themselves. For example, thiazidelike diuretics affect carbonic anhydrase in the kidney fold more, and also have a different effect on platelet aggregation and angiogenesis. However, the clinical significance of these differences is not fully known. Many of the data on the benefits of bendroflumethiazide came from old trials where doses of 10mg were used. There is no evidence for the use of bendroflumethiazide at 2.5mg showing improved clinical outcomes, although there are some trials showing it reduces blood pressure. Of course this doesn t mean it doesn t work, but why use a drug for which we haven t the evidence, when there are other drugs that have shown evidence of benefit? What do we do with people already on bendroflumethiazide? NICE say that there is no need to change for those established on bendroflumethiazide if their BP is controlled. Why are diuretics now only third line? NICE base this recommendation on a single trial: the ACCOMPLISH trial, and fully acknowledge this fact. ACCOMPLISH was a large RCT (over people) randomised to an ACE inhibitor and CCB, or an ACE inhibitor and thiazide diuretic and showed (NEJM 2008;359:2417): ACE + CCB was significantly more effective at preventing MI compared with ACE + diuretic (the trial was stopped early because of this).

11 There were also fewer withdrawals from the study on the ACE + CCB combination compared with ACE + diuretic, suggesting better tolerability. This contradicts the ALLHAT trial which showed that thiazides (in this case the thiazide-like diuretic chlortalidone) were as effective as ACE inhibitors and calcium channel blockers in preventing fatal and non-fatal cardiovascular endpoints (Circulation 2006;113:2201). However, in the ALLHAT trial drugs were being used predominantly as single agents, not in combination, as in the ACCOMPLISH trial. The ACCOMPLISH trial therefore probably better reflects real life situations where combination therapies are used. The relegation of diuretics to third line therapy is interesting because there is some evidence around their role in preventing the development of heart failure (and remember, hypertension is a major contributory factor in the development of heart failure). A meta-analysis of almost a quarter of a million patients with hypertension (in 26 trials), looked at which treatment of hypertension was most effective at reducing the development of heart failure and found that diuretics were the most effective drug at preventing heart failure (and better than ACE inhibitors or ARBs!)(Arch Intern Med 2010, doi: /archinternmed ). This is confirmed in a recent Cochrane review (Cochrane 2015 DOI: / CD pub2) and a massive meta-analysis (Lancet 2015, doi: /S (15) ). Are we missing a trick here? Should we be using thiazide-like diuretics sooner in hypertension? Step 4 therapy/resistant hypertension: what next? So your patient is on an ACE, calcium channel blocker and a thiazide-like diuretic but their clinic blood pressure is still >140/90. What do you do? NICE calls this resistant hypertension and recommends the following: Adding additional diuretic If serum potassium is 4.5mmol/l: add low dose spironolactone (25mg once daily). This is an unlicensed indication. Be particularly careful in those with reduced egfr because they are at increased risk of hyperkalaemia (see drug dilemma, below). If serum potassium is >4.5mmol/l: increase whichever thiazide-like diuretic you are using. When adding additional diuretic (regardless of type), monitor electrolytes and renal function after 1m (and again as clinically indicated). Add an alpha- or beta-blocker if additional diuretics are not tolerated or contraindicated. If BP not controlled on four drugs, seek specialist advice. A trial of 335 UK patients with resistant hypertension randomised people to spironolactone, bisoprolol, doxazosin (up to 8mg) or placebo. It was a cross over trial so each person took each drug for 12w (Lancet 2015;386:2059). Spironolactone was found to be the most effective treatment (average drop in BP 4mmHg compared to doxazosin or bisoprolol and 9mmHg compared with placebo). Six patients developed hyperkalaemia whilst on spironolactone (potassium >6). The authors suggested this may be to do with the importance of sodium retention in the aetiology/maintenance of hypertension. Renal denervation has been suggested as a treatment for resistant hypertension the idea is that it reduces the sympathetic drive from the kidneys that impacts on the cardiovascular system. Non-randomised trials and unblinded randomised trials have shown significant reductions in blood pressure. Then the first blinded RCT was published showing NO benefit (NEJM 2014;370:1393). A subsequent trial that of just 106 people did show a benefit showed a reduction in blood pressure sustained over 6m. Reviewers were blinded but patient s were not (NEJM 2015;385:1957). The jury is still out! However, this is the first blinded RCT to be published and it shows NO significant benefit. A reminder of why blinded RCT are the gold standard! Drug dilemma: spironolactone with ACE inhibitors/arbs As a result of 3 fatalities due to hyperkalaemia with concomitant spironolactone and ACE inhibitor/angiotensin receptor blocker (ARB) use, the MHRA have issued the following advice (MHRA Drug Safety Update February 2016): Concomitant use of spironolactone with ACE inhibitors/arbs is not recommended, especially if marked renal impairment. If co-administered use the lowest possible dose. Regularly monitor serum potassium and renal function (they don t specify what regularly means!). Stop treatment if hyperkalaemia occurs. What role for beta-blockers? Beta-blockers were the mainstay of hypertension treatment until the ASCOT trial showed that amlodipine (+ perindopril if needed) significantly reduced fatal and non-fatal CV endpoints compared to atenolol (+ bendroflumethiazide if required). This was despite the fact that BP reductions were similar between the two groups (just 2 3mmHg difference) (Lancet 2005;366:869). The ASCOT study led to beta-blockers being dropped as first line therapy.

12 However, a subsequent massive meta-analysis (almost half a million people in the RCT analysis and almost 1 million in the cohort analysis!) challenges this (BMJ 2009;338:b1665). This meta-analysis showed that: No one class of antihypertensive is much better or worse than any other. It showed that all classes of drugs achieved similar reductions in blood pressure. This translated into similar reductions in CV events for all classes of drugs, with a few exceptions, outlined below. The exceptions were: Calcium channel blockers (CCBs) seemed to reduce the incidence of CVA more than other classes of drugs, although this benefit was only slight (relative risk 0.92, CI ), or a 6% absolute reduction in events with CCBs compared to those on other classes of drug. This is possibly because CCBs reduce BP variability more than other antihypertensives. But it isn t all good news for CCBs: a small case-control study (only 350 cases) suggested that CCBs, when used with diuretics, increased the risk of MI compared to beta-blockers with diuretics, or ACE with diuretics (BMJ 2010;340:c103). This needs further testing in larger trials before we change our practice. Beta-blockers offer some protection against stroke, but less than the other drugs. This is in line with the findings of the ASCOT study (described above). However, when calcium channel blockers (which showed more benefit than other drugs) are removed from the analysis, any disadvantage from beta-blockers disappeared (relative risk for CVA 1.11, CI ). Another big meta-analysis also showed (Lancet 2015, doi: /S (15) ): Calcium channel blockers were better for stroke than other drugs Beta-blockers were slightly less effective against cardiovascular outcomes than other drugs. Diuretics were better at reducing the risk of heart failure than other drugs. The editorial accompanying this latter Lancet study suggested choosing blood pressure medication may be about thinking about which conditions someone is most at risk of (Lancet 2015,doi: /S (15) ). However, we should remember that few people are on a single antihypertensive, so initial choice of drug may be less critical than just getting on and lowering their blood pressure (almost regardless of means!). The latest NICE guidance recommends beta-blockers as fourth line agents after ACE inhibitors, calcium channel blockers and diuretics, except in certain situations: Women of child-bearing age Where ACE/ARBs are contraindicated/not tolerated Where there is evidence of increased sympathetic drive. How quickly do you get benefit from treatment? A massive meta-analysis showed that within 12m of starting drug therapy, benefits were seen in terms of reducing important endpoints (heart attacks and strokes) (BMJ 2009;338:b1665). This also applies to the elderly, as was shown in the HYVET trial, see below (NEJM 2008;358:1887). Should hypertension be treated differently in obese people? Should we use different anti-hypertensives in obesity? A massive meta-analysis of data suggests not! (Lancet 2015;385:867). Telemonitoring This trial took people with ABPM averages of / and randomised them to either usual care or telemonitoring. Telemonitoring involved doing weekly BP readings which were transmitted to a central hub. Participants then received s/text messages with feedback on their BP control and could contact their clinician for advice if they wanted to. The trial was small, only 200 in each arm, and lasted 6m, so they report on reductions in BP but not important cardiovascular outcomes (BMJ 2013;346:f3030). Those in the telemonitoring arm had slightly better BP control after 6m: with it being 4/2mmHg lower on average than those in the usual care group. The telemonitoring group were on more medications than at the start of the trial compared to usual care patients There was a small increase in GP/nurse contacts (1 additional GP visit, half a nurse visit and half a telephone consultation per patient on average). 3/200 patients reported significant anxiety from telemonitoring. The costs of the intervention was 109 of which 71 was equipment costs and the rest was GP/nurse/other NHS costs. So what does this mean in practice? The authors suggest further longer studies to look at whether this sort of monitoring would be clinically and cost-

13 effective outside the environment of a small trial, before widespread roll out. Take note clinical commissioning groups! Long term home monitoring: does it help reduce BP? Many of our patients buy BP monitors and measure their BP at home. A systematic review showed that home readings do reduce BP in the first 6m but not at 12m and by only a small amount (4/2mmHg) (Ann Int Med 2013;159:185). Additional interventions (nurse phone support, etc.) increase the benefits by about 4 8mmHg on the SBP, but cost more in time and money. What does this mean in practice? If people want to home monitor that is fine, but it may not improve their hypertension control! Hypertension in the elderly Many trials on hypertension (and most other conditions!) exclude the elderly, and yet in clinical practice we often then extrapolate data from these trials to our elderly population. Based on age alone, the elderly are at greater risk of stroke, but does treatment reduce this risk and what adverse effects may come from that treatment? This study, HYVET (Hypertension in the Very Elderly Trial), tries to answer just this (NEJM 2008;358:1887). HYVET study design Large RCT (>3800 patients), all over 80y, all with sustained systolic BP of >160. They were randomised to either: Diuretic (indapamide) or placebo. If target BP (150/80) not reached, ACE inhibitor (perindopril 2 or 4mg) or placebo added. Median follow-up was 1.8y. Analysis was on an intention to treat basis. Results We already know that older patients have a higher absolute risk of a cardiovascular event, therefore any relative risk reduction benefits older populations more. This study showed risk reductions in deaths from stroke and all cause mortality and a reduced incidence of heart failure, in line with previous evidence (e.g. ALLHAT). It did not reduce the risk of stroke overall (fatal and non-fatal). The benefits were apparent within a year of the study starting: important in an elderly population with a high risk of death from any cause. Adverse events were few. So we should take hypertension in the elderly seriously, and although we should consider individual patient factors, treatment is beneficial at reducing deaths from strokes, all causes and heart failure. What dose of antihypertensives? We have known for a long time that sub-maximal doses of beta-blockers give as good blood pressure control in hypertension as maximal doses with fewer side-effects. For example, atenolol 50mg is as good as atenolol 100mg, with fewer side-effects. Now evidence is emerging that this might be true for ACE inhibitors too. The systematic review included 92 RCTs (almost people) and showed that (Evidence-Based Medicine 2009;14:49): No ACE inhibitor was better than another. Lower than maximum doses resulted in significant falls in blood pressure. 1/8 1/4 of maximal doses resulted in 60 70% fall in BP compared to maximum doses. Half the maximum dose resulted in 90% fall in BP compared to maximum doses. Above maximum doses gave no more benefit than at maximum doses. Maximum doses of ACE inhibitors lowered: Systolic BP by about 7.7mmHg Diastolic BP by around 4.6mmHg. This raises the question of whether we should be routinely using lower doses of ACE inhibitors. NICE make no comment on this! Drug dilemma: simvastatin and calcium channel blockers and more When simvastatin is used with some drugs it is associated with an increased risk of myopathy and rhabdomyolysis. The MHRA have updated their recommendations about simvastatin use, and I have included it here because one of the drugs it affects is amlodipine,

14 which is widely used in hypertension (Drug Safety Update 2012;6(1)). Limit simvastatin dose to 20mg daily Contraindicated with simvastatin with these drugs: For fibrates: Amlodipine Diltiazem Verapamil Amiodaraone Gemfibrozil should not to be used with simvastatin Other fibrates can only be used if simvastatin dose is limited to 10mg maximum (except fenofibrate, which can be used with higher doses) Itraconazole Ketoconazole Erythromycin Clarithromycin HIV protease inhibitors Ciclosporin (This is not an exhaustive list but contains commonly used primary care drugs; see the Drug Safety Update for a comprehensive list.) Do also remember that grapefruit juice should not be taken with simvastatin or atorvastatin because it can lead to a significant increase in serum statin levels. Although NICE lipids guidance suggests atorvastatin should be used first lien for primary and secondary prevention, there are still large cohorts of people on simvastatin. The simplest thing to do is to switch those on simvastatin and amlodipine to atorvastatin (20mg for primary prevention, 80mg for secondary prevention). What we don t yet know is whether the MHRA will at some point say this interaction applies to atorvastatin too, and they might, as it is metabolised through the same pathway as simvastatin (pravastatin on the other hand is metabolised through a different pathway). Drug dilemma: diuretics and diabetes In those who are being treated for hypertension is it safe to use diuretics or might this increase the risk of diabetes? This review from the Uncertainties series in the BMJ (what a great name and what a useful series!) reviewed the evidence around this thorny issue (BMJ 2008;337:a679). The reviewers highlighted the following points: Thiazide and thiazide-like diuretics do slightly increase the risk of developing diabetes compared to calcium channel blockers or ACE inhibitors. BUT for those who did develop diabetes the cardiovascular outcomes (risk of MI, CVA) were the same as, or better than those on alternative drugs. These findings have been confirmed in other studies (e.g. SHEP, which importantly had a long-term (14y) follow-up). How can this be? Lowering blood pressure may reduce CV endpoints by such an extent that it compensates for those who develop diabetes as a result of the drugs. As the authors point out, what we really need is an RCT that is designed to answer this question. The NAVIGATOR observational cohort study suggested that in those with impaired fasting glucose, the NNH for diuretics was in the region of 17 (9 68) over 5y (discussed above, BMJ 2013;347:f6745). The same paper quotes data from other studies, suggesting that the NNH for diuretics in those WITHOUT impaired glucose was 167 after 4y treatment. Drug dilemma: spironolactone and trimethoprim Both trimethoprim and spironolactone can cause hyperkalaemia. A case control study suggests that adding trimethoprim in those on spironolactone may significantly increase the risk of hyperkalaemia (BMJ 2011;343:d5228). The authors suggest that 60% of admissions to hospital with hyperkalaemia in the elderly could be avoided if trimethoprim was not used in those on spironolactone. The authors think the risk is lower in younger people. Nitrofurantoin was also associated with an increased risk, although this was much lower than that for trimethoprim. This study could be criticised because it was based on administrative data rather than actual lab results, but the increased risk they calculated is significant. Do you use trimethoprim in those on spironolactone? Should you swap to nitrofurantoin or an alternative? Drug dilemma: spironolactone and breast cancer Spironolactone affects hormonal receptors, and it has been postulated that this could increase the risk of breast cancer in women. However, a large cohort study of women aged over 55 using spironolactone showed no increased risk of breast cancer (BMJ 2012;345:e4447). Drug dilemma: ACE inhibitors, ARBs and pneumonia A systematic review has suggested that:

15 ACE inhibitors may protect people against pneumonia. The NNT is 65 (CI ) over 2y, that is for every 65 people treated with an ACE over 2y, one pneumonia would prevented compared to placebo (BMJ 2012;345:e4260). Those who had had a stroke had even more benefit. Asian people (compared with non-asians) seemed to get more benefit. ARBs probably don t protect against pneumonia. There are a number of cautions when interpreting the evidence: None of the trials set out to look at pneumonias, rather pneumonias were reported as adverse events in trials done looking at CV benefits of ACE inhibitors. The systematic review pooled data from RCTs, case control studies and cohort studies. The reduction in pneumonias was seen only in the case control and cohort studies, not in the RCTs, which would be considered higher quality trials. Most of the data come from unpublished trials. Why? One possibility is that the cough triggered by ACE inhibitors helps to keep the respiratory tree free of inhaled/aspirated organisms. Genetic variations in response to bradykinins (a key chemical triggering the cough) may explain why Asian patients get more benefit, although this has not been proved. What does this mean in practice? The accompanying editorial reminds us that we should not start using ACE inhibitors to prevent pneumonia, even in high risk groups, or suggest ACE users with a cough put up with it for the sake of fewer pneumonias(!), until we have a better understanding of the mechanism and more proof this finding is real (BMJ 2012;345:e4566). Drug dilemma: antihypertensives and gout - BMJ 2011;344:d8190 It has long been known that hypertension increase the risk of gout (possibly through renal changes in hypertension). Now a large case control study has shown that some antihypertensives increase this risk further. It showed that those with hypertension had differing risks of gout depending on the drugs they were on. Those on calcium channel blockers and losartan had a lower incidence of gout (unsurprisingly, these drugs are known to lower urate levels) than those on other angiotensin receptor blockers, ACE inhibitors, diuretics or beta-blockers. Other risk factors were controlled for. As the accompanying editorial points out, reducing serum uric acid levels may reduce cardiovascular end points as well as reducing gout-related morbidity (BMJ 2012;344:d7961). This might be a reason to use calcium channel blockers and losartan in those with known gout. Drug dilemma: antihypertensives and dementia A study of over people (only 2% were women!) with cardiovascular disease aged over 65y has looked at the impact of antihypertensives on the incidence of dementia over 4 years (BMJ 2010;340:paper b5465, editorial b5235). The study showed that ARBs and ACE reduced the incidence of dementia compared to other cardiovascular drugs. Hazard ratio for ARBs 0.76 (CI ) Hazard ratio for ACE 0.81 (CI ) Hazard ratio for those on ARBs and ACE 0.54 (CI ) Those with dementia at the start of the study were also less likely to be admitted to a nursing home if they were taking ARBs or ARBs and ACE inhibitors (hazard ratio 0.51, CI ). However, as the editorial points out, there are a number of problems with this study: This was a cohort study, not an RCT. 98% were men, so the impact on women is unknown. The comparator (other cardiovascular drugs) is rather vague! It would be ethically difficult to disallow use of other cardiovascular groups, but to allow such a wide spectrum isn t helpful. So what does this mean in practice? Not time to offer ARBs and/or ACE to all as dementia prophylaxis until we have better evidence. Drug dilemma: antihypertensives and fractures A study looked at the risk of hip fractures in elderly people (mean age 81y) living at home in the initial phase of starting antihypertensives (Arch Intern Med 2012;172:1739). They found that, when compared to the time before and the time after they were established on antihypertensives, there was an increased risk of hip fracture (from falls) in the first 45d of taking

16 antihypertensives (about 1.4x more likely, although I can t calculate NNTs from the data). There were not huge differences in the data between different classes of antihypertensives. So the HYVET trial (above) suggests significant benefit from treating hypertension and this study reminds us to be aware that there are some risks perhaps a reminder to go slow when starting! Potato consumption and hypertension A prospective US cohort study has shown that higher potato consumption (whether baked or boiled) increases the risk of hypertension in women, but not in men (BMJ 2016;353:i2351 and editorial i2442). Unsurprisingly consuming potatoes as chips increased the risk of hypertension in both men and women. Bizarrely crisp consumption was associated with lower blood pressure, perhaps a reminded of the challenges of unpicking the impact of a single food source on diet! Why? The authors suggested that this may be to do with the glycaemic load from the potatoes (although the editorial is less convinced by this argument, pointing out glycaemic load varies between potato varieties, and is significantly affected by the other foods eaten with the potatoes). Alternatively potato consumption may be a marker of other dietary habits that also increase hypertension risk. Or it could be that potato consumption increased weight, which in turn increases the risk of hypertension. Pasta anyone? Hypertension Ambulatory blood pressure is now the diagnostic investigation of choice for hypertension. Clinic BP readings are no longer recommended for the diagnosis of hypertension, however, they can (and should) be used to monitor responses to treatment. Hypertension is now defined as stage 1 and stage 2. All those with stage 2 disease should be offered anti-hypertensives, but only some of those with stage 1 hypertension should be offered anti-hypertensives. The threshold BP for offering drug therapy has changed, partly reflecting the move to ambulatory BP monitoring. Diuretics have moved to third line drugs after ACE inhibitors and calcium channel blockers The thiazide-like diuretic of choice is now indapamide rather than bendroflumethiazide or hydrochlorothiazide. However those already established on bendroflumethiazide or hydrochlorothiazide need not be changed to indapamide. Be mindful of the new recommendations around the maximum dose of simvastatin to use with amlodipine and other drugs. There is increasingly mixed evidence on whether treating mild hypertension is beneficial or not. A reminder that hypertension is a risk factor not a disease. Do we reflect this in our conversations with patients? With time we may move to more sophisticated ways to decide on who should be offered treatment based on starting CVD risk, but we are not there yet. Is it time to update your practice protocol? There s a starting point (our own practice protocol) in the Appendix if that helps. How will you ensure your patients are not taking simvastatin above the recommended dose with other drugs, particularly the calcium channel blocker? Do you need to run a search and identify those affected and make a change to their medication? For professionals: The British Hypertension Society website lists machines that have been validated for ambulatory and home readings, although I note it hasn t been updated for some time: We make every effort to ensure the information in these pages is accurate and correct at the date of publication, but it is of necessity of a brief and general nature, and this should not replace your own good clinical judgement, or be regarded as a substitute for taking professional advice in appropriate circumstances. In particular check drug doses, side effects and interactions with the British National Formulary. Save insofar as any such liability cannot be excluded at law, we do not accept any liability for loss of any type caused by reliance on the information in these pages. GP Update Limited May 2017

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