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Earn 3 CPD Points online The underestimated risk of hypertension Dr David Webb Johannesburg Introduction The high and increasing worldwide burden of hypertension is a major global health challenge.

1 Earn 3 CPD Points online The underestimated risk of hypertension Dr David Webb Johannesburg Introduction The high and increasing worldwide burden of hypertension is a major global health challenge. Hypertension increases morbidity and mortality from cardiovascular (CV) and kidney diseases and is responsible for significant financial costs to society. Ischaemic heart disease and stroke, a substantial proportion of which is attributable to hypertension, are the leading causes of death worldwide, accounting for approximately one in four deaths. Most people with clinical hypertension have additional CV risks and/or evidence of blood pressure-related damage (heart disease, stroke and kidney damage). Without effective early intervention to improve blood pressure control, the global epidemic of CV and kidney disease is expected to continue to increase, especially in low- and middle-income countries. 1,2 KEY MESSAGES Only one in five South Africans diagnosed with and treated for hypertension is under control Women are more aware of hypertension as a health problem and are twice as likely as men to seek treatment The greatest success achieved with blood pressure lowering is seen in patients with lowmoderate risk before hypertensive organ damage occurs Intervene earlier and avoid progression to high risk More intense blood pressure reduction is associated with a significantly lower risk of stroke (29%) A recent meta-analysis of more than patients showed the relative strengths of different classes of antihypertensive agents that can help to guide choice of therapy This report was made possible by an unrestricted educational grant from Zentiva/Sanofi. The content of the report is independent of the sponsor. Clinical studies support the use of combination therapy with either an angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), plus either a diuretic and/or calcium channel blocker (CCB) as rational first-line and second-line therapy. Prevalence of hypertension In 2010, the estimated global agestandardised prevalence of hypertension in adults aged 20 years was approximately 30%. Approximately three-quarters of hypertensive individuals live in low- and middle-income countries, where the number of adults with hypertension (1.04 billion) is almost three times that in high-income countries (349 million). In low-, middle- and high-income countries, hypertension prevalence increases with age (Table 1). Between the years 2000 and 2010, the overall global prevalence of hypertension increased by 5.2%. However, the prevalence in high-income countries decreased by 2.6%, whereas in low- and middleincome countries it increased by 7.7%. 1 january

2 Table 1. Prevalence of hypertension in Age (years) High-income countries Low- and middle-income countries Men (%) Women (%) Men (%) Women (%) Overall Hypertension awareness, treatment and blood pressure control Worldwide, less than half of hypertensive adults are aware of their condition. Although the majority of those who are aware of their hypertension are receiving treatment, blood pressure control rates are poor, with fewer than one in six controlled to acceptable levels. In comparison with high-income countries, awareness, treatment and control are all substantially lower in low- and middleincome countries, including South Africa (Tables 2 and 3). 1,3 Table 2. Proportions of awareness, treatment and blood pressure control in Region Awareness Treatment Control High-income countries 67.0% 55.6% 28.4% Low- /middle-income countries 37.9% 29.0% 7.7% Table 3. Gender-specific hypertension awareness, treatment and control in 2010 in South Africa 1 Awareness Treatment Control (among treated) Control (among those with hypertension) Men Women Men Women Men Women Men Women Impact of hypertension Hypertension is the leading risk factor for death and disability globally. 4 It is responsible for 50% of heart disease, stroke and heart failure. Overall, hypertension accounts for 18% of all deaths and for more than 40% of deaths among people with diabetes. It is the leading risk for foetal and maternal death in pregnancy and also for death among those with dementia or renal failure. 2 In people aged 30 years, hypertension (blood pressure 140/90mmHg or receiving blood pressure-lowering medication) is associated with an overall lifetime risk of CV disease of 63%, compared with 46% for those with a normal blood pressure; hypertensive individuals tend to develop CV disease on average five years earlier. 5 2 january 2018

3 Effect of hypertension treatment on CV outcomes Meta-analyses of randomised controlled clinical studies of antihypertensive treatment indicate that reducing blood pressure in hypertensive individuals significantly reduces the risk of CV outcomes, CV-related deaths and all-cause mortality (Table 4). For every 1000 people treated with antihypertensive therapy for five years, an average blood pressure reduction of 10/5mmHg would prevent 28 cardiovascular events. 6 Although greater blood pressure reductions are associated with greater risk reduction, the relationship is not proportional or linear. Progressively lower reduction results in progressively lower increments in risk reduction. 6,7 Table 4. Relative and absolute risk reduction of various outcomes in blood pressurelowering trials. Standardised risk reduction is to a SBP/DBP reduction of 10/5mmHg Outcome Relative risk reduction Absolute risk reduction (per 1000 patients treated for five years) Number needed to treat Stroke 36% Coronary heart disease 16% Heart failure 43% CV events* 25% CV death 18% All-cause death 11% SBP: systolic blood pressure; DBP: diastolic blood pressure *Composite of stroke, coronary heart disease and heart failure All grades of hypertension are similarly susceptible to the beneficial effects of blood pressure lowering. Consequently, antihypertensive treatment should be considered for all adult individuals whose blood pressure values remain 140/90mmHg, despite adequate lifestyle interventions. Furthermore, recognising the benefit of treating blood pressure in patients with grade 1 hypertension is important, because the majority of those seeking counselling about drug treatment initiation fall into this group and their total CV risk is usually considered to be low to moderate (risk of CV death <5% in 10 years). 7 Antihypertensive therapy and residual risk Relative risk reduction for CV events with antihypertensive therapy is fairly constant, regardless of the level of baseline blood pressure and baseline risk. Accordingly, absolute risk reductions increase significantly with increasing level of baseline CV risk (Table 5). However, with higher baseline risk, the residual risk remaining after initiation of antihypertensive treatment will also be greater. Consequently, if the success of antihypertensive therapy is measured not only by prevention of CV events (risk reduction), but also by absolute level of treatment failures (residual risk), then it is clear that the greatest success of blood pressure lowering is achieved in patients with low-moderate risk, before hypertensive organ damage occurs (only 34 instead of 218 major CV events occurring per 1000 patients treated for five years). 7,8 january

4 Table 5. Absolute risk reduction and residual risk in blood pressure-lowering trials according to baseline CV risk (for composite of stroke, coronary heart disease or heart failure). Standardised risk reduction is to a SBP/DBP reduction of 10/5mmHg 8 Baseline CV risk Absolute risk reduction/nnt (per 1000 patients treated for five years) Residual risk (per 1000 patients treated for five years) Odds ratio (95% CI) vs low-moderate baseline risk Low-moderate risk (<5%) High risk (5% to <10%) Very high risk (10% to <20%) Very, very high risk ( 20%) -7 NNT = NNT = NNT = NNT = ( ) ( ) ( ) How can residual risk be reduced? Intervene earlier and avoid progression to high risk In addition to hypertension, major contributors to global mortality include tobacco smoking (including second-hand smoke), a diet low in fruit and vegetables and high in sodium, high body mass index, physical inactivity and high fasting plasma glucose. 4 Educating and assisting the population in general remains paramount in helping people to maintain a More intense blood pressure reduction (lower target) healthy body weight, physical activity and healthy nutrition as they get older. As discussed above, where pharmacological intervention is necessary, starting treatment earlier when baseline risk is still lower, rather than later, may yield significantly greater returns in terms of CV disease reduction. In a meta-analysis of randomised controlled clinical trials published between 1966 and 2015, more intense blood pressure lowering was associated with a significantly lower risk of stroke (29%), coronary events (20%), major CV events (25%) and CV mortality (21%), but not heart failure or all-cause death. Considering three levels of target systolic blood pressure (150mmHg, 140mmHg and 130mmHg), reducing blood pressure with a difference of -10/-5mmHg across each cut-off yielded a similar relative risk reduction, but a lower absolute risk reduction at the lower cut-offs (due to a progressively lower level of baseline risk; Table 6). 9,10 Table 6. Relative and absolute risk reduction of CV events (composite of stroke, coronary heart disease and heart failure) in blood pressure-lowering trials. Standardised risk reduction is to a SBP/DBP reduction of 10/5mmHg 10 Blood pressure cut-off (mmhg) Relative risk reduction Absolute risk reduction (per 1000 patients treated for five years) NNT vs vs <130 vs january 2018

5 Does the type of initial antihypertensive therapy matter? In meta-analyses of 55 eligible randomised clinical trials comparing different antihypertensive monotherapies and including more than patients and more than one million patient years, all antihypertensive drug classes were associated with similar positive outcomes (reduction in stroke and major CV events) when blood pressure-lowering efficacy was equivalent. 11 However, when compared to all other classes together, there were some differences noted for each of the monotherapy classes, which might be important when considering antihypertensive therapy for specific individual patients: Diuretics were superior in preventing heart failure; Beta-blockers were less effective in preventing stroke; Calcium channel blockers (CCBs) were superior in preventing stroke and all-cause death, but inferior in preventing heart failure; Angiotensin-converting enzyme inhibitors (ACE-inhibitors) were more effective in preventing coronary heart disease and less effective in preventing stroke; Angiotensin receptor blockers (ARBs) were less effective at preventing coronary heart disease; Renin-angiotensin system blockers (ACE-inhibitors and ARBs) were more effective in preventing heart failure; Baseline CV risk had no effect on the effectiveness of any drug class. The meta-analysis confirms guideline recommendations that the main goal of antihypertensive treatment is blood pressure lowering with the aim of achieving and maintaining a specific goal blood pressure. Choice of antihypertensive treatment should be individualised according to response to the individual agent and tolerability. If it is suspected that the patient may be at higher risk of a specific CV outcome, then the observations above might help to direct therapy. Similarly, possible differences in the effects of the various antihypertensive classes on onset and progression of organ damage may also be taken into account. Combination therapy The majority of hypertensive patients need two or more antihypertensive agents to reach blood pressure targets. As an estimate, one-third may be successfully treated with monotherapy, one-third may require two and the remaining one-third of patients will need three or more antihypertensive agents for effective blood pressure control. 12 When monotherapy fails to control blood pressure, switching to another antihypertensive (sequential monotherapy) or serially increasing the dose of the initial antihypertensive drug is no longer recommended, since patients who fail a trial of monotherapy are more likely to respond to a combination of low-dose antihypertensive drugs. When combination therapy is required then two drugs should be selected that have both complementary mechanisms of action and, if possible, complementary effects on different CV outcomes. Table 7. Recommended combination therapy for patients with hypertension A: ACE-inhibitor or ARB; C: CCB; D: thiazide-type diuretic Younger patients (<60 years of age) Older and black patients Proportion of patients controlled on therapy Step 1 A C or D 20-25% Step 2 A + C or A + D 60% Step 3 A + C + D 80-90% Step 4 Step 5 Add aldosterone antagonist Add alpha-blocker, beta-blocker, investigate for secondary causes, refer january

6 Table 7 lists combination antihypertensive therapies that are recommended based on results from clinical trials. Clinical studies support the use of an ACE-inhibitor or ARB plus either a diuretic and/or CCB as rational initial and second-line choices for combination therapy. Both diuretic and CCB combinations have been shown to reduce the incidence of CV morbidity and mortality in primary and secondary prevention studies in comparison with monotherapy and alternative combinations In contrast, combining an ACE-inhibitor with an ARB conferred no benefit in comparison to ACE-inhibitor or ARB monotherapy, but was associated with an increase in adverse effects. 26 Hypertension that is resistant to treatment with three or more blood pressure-lowering medications is estimated to occur in approximately 10% of treated hypertensive patients and is associated with a poor prognosis. On the basis that treatment resistance might be explained by sodium retention, the PATHWAY-2 study compared spironolactone (a mineralocorticoid receptor-blocking agent) with alternative fourth-line treatments (alpha- 1-adrenoceptor blocker, doxazosin and the beta-1-adrenoceptor blocker, bisoprolol) as add-on therapy in patients with uncontrolled blood pressure on triple therapy with an ACE-inhibitor or ARB plus a CCB and diuretic. Spironolactone was the most effective treatment and was well tolerated, with a low rate of adverse events and withdrawals due to adverse events. 16 Statin therapy The ASCOT-LLA study compared antihypertensive treatment with or without atorvastatin in patients with a baseline total cholesterol level of 6.5mmol/l. It was stopped prematurely after a median of 3.3 years follow-up because of substantial CV benefits in the group of patients assigned to atorvastatin. After both two years and 11 years follow-up, the benefits of early introduction of the statin remained, even among those who Conclusions Hypertension and other modifiable risk factors for CV disease remain a significant and urgent cause for concern the world over. Many of these risk factors are related to lifestyle and it is not uncommon for individuals to already have multiple risk factors when they first consult their doctor, and when the opportunity for early intervention has already been missed. Addressing CV risk once it has escalated to moderate or high risk, even with the most effective treatments, leaves a residual risk that far exceeds had discontinued statin therapy Similarly, low-dose rosuvastatin significantly reduced the risk of CV events in an ethnically diverse population without CV disease, but with at least one CV risk factor. In comparison with placebo, the composite endpoint of CV death, nonfatal myocardial infarction or nonfatal stroke was reduced by 24% among patients receiving rosuvastatin, regardless of baseline blood pressure levels. 31 that associated with untreated lower risk levels. Therefore, preventing CV disease starts with education and urging people to adhere to a healthier lifestyle in terms of physical activity and nutrition. Use of aggressive pharmacotherapy, for example combination antihypertensive treatment combined with other appropriate medication such as statins, should be borne in mind when making early treatment decisions, when the benefits are greater and more sustained than if it is left until later or used as a last resort. 6 january 2018

7 References 1. Mills KT, Bundy JD, Kelly TN, et al. Global disparities of hypertension prevalence and control. A systematic analysis of population-based studies from 90 countries. Circulation 2016; 134: Campbell NRC, Lackland PH, Niebylski ML, et al. High blood pressure: why prevention and control are urgent and important - A 2014 Fact Sheet from the World Hypertension League and the International Society of Hypertension. J Clin Hypertens 2014; 16(8): Chow CK, Teo KK, Rangarajan S, et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and lowincome countries. JAMA 2013; 310(9): Lim S, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, : a systematic analysis for the Global Burden of Disease Study Lancet 2012; 380(9859): Rapsomaniki E, Timmis A, George J, et al. 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Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359(9311): PROGRESS Collaborative Group. Randomised trial of a perindopril based blood pressure lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370: The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: Chalmers J, Arima H, Woodward M, et al. Effects of combination of perindopril, indapamide, and calcium channel blockers in patients with type 2 diabetes mellitus. 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25. Jamerson K, Weber MA, Bakris GL, et al. ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008; 359: 2417-2428.

8 25. Jamerson K, Weber MA, Bakris GL, et al. ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008; 359: ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: Sever PS, Dahlof B, Poulter NR, et al. ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial: Lipid Lowering Arm (ASCOT-LLA): multicentre randomised controlled trial. Lancet 2003; 361: Sever PS, Poulter NR, Dahlof B, et al. The Anglo- Scandinavian Cardiac Outcomes Trial lipid-lowering arm: extended observations 2 years after trial closure. Eur Heart J 2008; 29(4): Holdaas H. Statin therapy for prevention of coronary artery disease. The earlier the better or the longer the better? Eur Heart J 2008; 29(4): Sever PS, Chang CL, Gupta AK, et al. The Anglo- Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the UK. Eur Heart J 2011; 32: Yusuf S, Bosch J, Zhu J, et al. Cholesterol-lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374: This article was written for DeNovo Medica by Dr David Webb, based on a presentation by Professor JA Ker at a cardiovascular risk meeting held at Three Rivers Lodge, Vereeniging. Earn CPD points online Visit Log in or register and start earning CPD points today. Certificates will be ed to you. Disclaimer The views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities. Published by 70 Arlington Street, Everglen, Cape Town, 7550 Tel: (021) I info@denovomedica.com 8 january 2018

Clinical Updates in the Treatment of Hypertension JNC 7 vs. JNC 8. Lauren Thomas, PharmD PGY1 Pharmacy Practice Resident South Pointe Hospital

Clinical Updates in the Treatment of Hypertension JNC 7 vs. JNC 8 Lauren Thomas, PharmD PGY1 Pharmacy Practice Resident South Pointe Hospital Objectives Review the Eighth Joint National Committee (JNC