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BR 04-1MANAGEMENT OF TREATMENT-RESISTANT HYPERTENSION.

Treatment-resistant hypertension (TRH) is defined as the failure to achieve an office BP target of <140/90 mmHg (<130/80 mmHg in patients with chronic kidney disease (CKD) or diabetes) in patients with hypertension (HT), despite adherence to at least 3 antihypertensive medications at optimal tolerated doses, ideally including a diuretic (Calhoun et al., Circulation 2008). TRH identifies patients with hard-to-treat HT, who might benefit from specialist investigation and treatment. Although some studies put the prevalence of TRH as >10%, these levels may be inflated by white-coat hypertension and poor adherence. Indeed, PATHWAY-2 (Williams et al., Lancet 2016) and SYMPLICITY HNT-3 (Bhatt et al., NEJM 2014) suggest that true TRH is rarer than generally thought. Risk factors for TRH (which themselves increase cardiovascular risk) include obesity, older age, African ethnicity, CKD and diabetes. Although not fully addressed, evidence suggests that prolonged poorly controlled BP in TRH has a poor outcome.Before diagnosing TRH, pseudo-resistant HT must be excluded. Poor adherence to treatment - which may be caused by side-effects, complicated dosing schedules, pill burden, poor doctor-patient relationship, poor understanding or acceptance of the need for treatment, and medication cost -is common, with up to 40% of newly diagnosed hypertensive patients discontinuing medications within a year. Directly observed therapy and urine drug screens can be very helpful in its detection. Poor office BP measurement technique is another common problem. Sufficient rest, use of the right cuff, and repeated automated measurement in a quiet setting, is critical. ABPM (or at least home BP measurement) is crucial to excluding 'white coat' HT. In those diagnosed with true TRH, modifiable causes must be excluded, including diet, drugs, secondary endocrine and renal causes, and sleep apnoea. In most cases, however, the aetiology of TRH is multifactorial and treatment aimed at multiple targets.Treatment of TRH includes appropriate life-style change (focused on diet, salt intake, exercise, weight), withdrawal or minimization of offending drugs (including alcohol), and the use of effective multi-drug regimens. Pre-existing drug treatment should ideally combine a thiazide-like diuretic (TLD), calcium channel blocker, and ACE inhibitor/ARB. Optimising diuretic use appears very important, so use of a long-acting TLD, such as chlortalidone or indapamide, may help. Loop diuretics should be considered in CKD patients. Low-dose spironolactone (25 mg, increased to 50 mg, once daily) or eplerenone (both mineralocorticoid receptor antagonists) are now guideline approved as suitable 4th line agents in patients with TRH. Their success may be accounted for by the elevated aldosterone levels frequently found in TRH, either through undetected primary hyperaldosteronism or because aldosterone secretion escapes renin-angiotensin system blockade. Vital new evidence for the effectiveness of spironolactone in TRH comes from PATHWAY-2 (Williams et al., Lancet 2016). This randomised double-blind crossover trial involved sequential treatment with spironolactone (n = 285), an α1 blocker doxazosin (n = 282), β blocker bisoprolol (n = 285) and placebo (n = 274), each for 12 weeks. Spironolactone led to significantly greater mean reductions in systolic blood pressure than placebo (-10 [-11.7 to -8.74] mmHg, p < 0.001), doxazosin (-5.64 [-69.1 to -4.36], p < 0.001) and bisoprolol (-5.98 [-7.45 to -4.51] mmHg, p < 0.0001) on home systolic BP readings taken at the final visit of each treatment cycle. The magnitude of BP lowering with spironolactone was inversely proportional to plasma renin concentration, an association not observed with either bisoprolol or doxazosin, supporting the role of sodium retention, volume expansion and low plasma renin in TRH. As well as clearly demonstrating the superiority of spironolactone in TRH, the drug was shown to be safe and well tolerated with no greater discontinuation rate due to renal impairment and hyperkalaemia than with the other treatments.An alternative promising approach is the use of endothelin (ET) receptor antagonists. These drugs, which block the vasoconstrictor, inflammatory and pro-atherogenic actions of ET-1, also reduce BP and proteinuria in CKD (Davenport et al., Pharmacol Rev 2016). Clinical trials have shown their efficacy in TRH (Weber et al., Lancet 2009), and phase 3 trials are currently ongoing in patients with diabetic nephropathy. Other drugs, such as b-blockers, a-blockers, centrally acting agents such as moxonidine or potent vasodilators, including hydralazine or minoxidil, may be considered in a multi-drug approach, depending on the clinical circumstances. The only combination that cannot be recommended is the addition of a second agent to block the renin-angiotensin system, with evidence of increased renal failure with the combination of ACE-I + ARB or ARB + renin inhibitor.Two promising non-pharmacological therapies have been under evaluation for the treatment of TRH - renal denervation (RDN) and baroreflex activation therapy (BAT). These are attractive targeted interventional options, with considerable underpinning evidence that sympathetic overactivity contributes to raised BP. However, when the first blinded and randomised study with RDN was performed, SYMPLICITY HNT-3 (Bhatt et al., NEJM 2014), it did no better than the sham procedure. Technically, it will be significantly easier to do randomised and blinded studies with BAT. However, currently, given their potential for adverse effects, and the lack of evidence of efficacy, RDN and BAT should only be used in the context of ongoing clinical research.This is an exciting time in the management of TRH. Spironolactone shows clear superiority to other standard treatments, and supports the case for excess sodium as a component of TRH. Other agents, such as ET antagonists, show promise. The results of SPRINT (The SPRINT Research Group, NEJM 2015) suggest we may need new lower targets for BP control, so TRH will become an increasing challenge. We also need good research on the risks of TRH, and what target blood pressures provide optimal outcomes.

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