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Resistant hypertension: an approach to management in primary care

Resistant hypertension: an approach to management in primary care Family Practice Resistant hypertension: an approach to management in primary care 1 2 Julian P. Yaxley , Sam V. Thambar 1 2 Department of Medicine, Redcliffe Hospital, Department of Medicine, Gold Coast University Hospital, Queensland, Australia A b s t r Ac t Hypertension is widely encountered in family medicine. Despite its prevalence, many patients have uncontrolled or difficult‑to‑control blood pressure. Resistant hypertension is defined as hypertension that is poorly responsive to treatment and requires the use of multiple medications to achieve acceptable blood pressure ranges. It may be a consequence of secondary hypertension or have no identifiable cause. Resistant hypertension is important to recognise because it places patients at risk of end‑organ damage. Primary care physicians should be aware of the therapeutic approach for hypertension when traditional therapy fails. This article aims to familiarise readers with the evaluation and management of resistant hypertension by outlining the most recent evidence‑based treatment options. Keywords: Blood pressure, cardiovascular disease, renal denervation, resistant hypertension [6,7] of whom are poorly controlled. Its prevalence is likely to Introduction [8] continue rising. Hypertension is defined  as persons 18 years of age and over  with a systolic pressure reading of 140 mmHg or more or It is estimated that approximately 10% of hypertensive patients [9,10] a diastolic reading of 90 mmHg or more, or those taking in westernised countries have resistant hypertension. Doctors [1,2] antihypertensive medications. Between 90‑95% of cases in primary care can expect to encounter resistant hypertension are essential hypertension in which there is no identifiable   one in every 20 hypertensive patients, compared with higher [3] [10] cause. The remaining cases of hypertension are secondary to a rates in specialist clinics. distinguishable process and would likely resolve if the underlying condition was treated. Aetiology and pathogenesis In most cases the pathogenesis of resistant hypertension is A considerable number of patients fail to reach target blood uncertain. Only in a minority of instances is the problem due  pressure ranges despite lifestyle advice and standard medical to secondary hypertension. In the absence of a secondary therapy. Resistant hypertension is defined  as blood pressure  cause the condition is most likely multifactorial. Proposed that remains above 140/90 mmHg despite use of three mechanisms include genetic factors, aberrant sympathetic antihypertensive medications of different classes at the best nervous system activation and altered renal sodium and water [4,5] tolerated doses, one of which must be a diuretic. handling due to changes in the renin‑angiotensin‑aldosterone system. Epidemiology Hypertension is widely encountered in primary care and is the Clinical features and diagnosis [1] most common condition managed at primary care level. It Although hypertension is usually asymptomatic detection and [2] accounts for 8.6% of all visits to a primary care physician. treatment remains important. Uncontrolled blood pressure is a Hypertension affects 32% of adults in western society, two‑thirds considerable cardiovascular risk factor that makes target‑organ [11] damage more likely. Possible end‑organ consequences of Access this article online untreated hypertension include heart failure, stroke, ischemic Quick Response Code: Website: heart disease and renal failure. www.jfmpc.com Address for correspondence: Dr. Julian P. Yaxley, Department of Medicine, Redcliffe Hospital, DOI: 10.4103/2249-4863.154630 Queensland, Australia. E‑mail: [email protected] Journal of Family Medicine and Primary Care 193 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension Resistant hypertension presents in patients who have persistently Further screening investigations for secondary causes are elevated blood pressure which responds minimally to therapy. not compulsory. Additional tests [Table 3] should be chosen Approximately six months of treatment with three conventional depending on the clinical circumstances of the patient as revealed antihypertensive agents should be allowed for at least some blood by history and examination. [9] pressure correction. If at six months treatment is proving Finally, all patients with ongoing uncontrolled hypertension unsuccessful the possibility of resistant hypertension may be should be assessed routinely for any signs of end‑organ contemplated. compromise. This may include measures such as yearly fundoscopy, electrocardiogram and urine dipstick. The true prevalence of resistant hypertension is difficult  to  quantify because many patients actually suffer ‘pseudo‑resistant’ hypertension. Pseudo‑resistant hypertension refers to poorly Management controlled disease which appears resistant but is actually Primary care physicians are familiar with the management of attributable to other factors. The commonest reasons for essential hypertension. Treatment should comprise both lifestyle apparent treatment resistance are medication non‑compliance modification  and pharmacologic therapy. The blood pressure  and insufficient  drug therapy. Other implicated factors include  goal in uncomplicated patients is 140/90 mmHg which could [17] failure to adhere to lifestyle advice, poor measurement technique, be relaxed to 150/90 in patients greater than 60 years of age. whitec ‑ oat hypertension and the use of medications that interfere A more appropriate treatment target in patients with end‑organ [5,15] with blood pressure [Table 1]. damage is 130/80 mmHg. A key step in diagnosing resistant hypertension is confirming  Non‑pharmacological treatment that blood pressure elevation is truly resistant. Pseudo‑resistance Non‑pharmacologic measures should be introduced in patients must be ruled out with a thorough history and medication with hypertension of any severity. Recommendations include review, followed by measurement of blood pressure with proper technique. Provided these confounders are absent and standard Table 1: Drugs that interfere with blood drug therapy has failed, resistant hypertension is diagnosed. [10] pressure control Non‑steroidal anti‑inflammatories Every patient with resistant hypertension requires at least some Oral contraceptives screening for secondary causes [Table 2]. Obstructive sleep  Corticosteroids apnoea, chronic kidney disease and primary hyperaldosteronism Tricyclic antidepressants [12] are the most frequent comorbidities. Although secondary Monoamine oxidase inhibitors hypertension is more likely in resistant hypertension than in Other substances‑caffeine, cocaine, alcohol patients whose blood pressure is controlled, most still do not [13] have an identifiable cause. [10] Table 2: Causes of secondary hypertension Evaluation for secondary causes should include comprehensive Chronic kidney disease Renovascular disease history and physical examination searching for any clues pointing Obstructive sleep apnoea towards to an underlying diagnosis. For example the patient may Coarcation of the aorta have symptoms of obstructive sleep apnoea, or alternatively Pheochromocytoma episodic palpitations with headaches and diaphoresis might Primary hyperaldosteronism suggest pheochromocytoma, while an abdominal bruit could Cushing’s syndrome indicate renal artery stenosis. Oftentimes however, the clinical  Thyroid disease assessment will be unremarkable. Intracranial mass Beyond history and examination, all patients with resistant hypertension should be investigated at minimum with a serum Table 3: Initial investigations for suspected causes of [10,16] creatinine test, estimated glomerular filtration  rate and urine  secondary hypertension [10] dipstick. This is due to the high prevalence of chronic kidney Disorder Suggested investigation disease in this population. Any derangement in these baseline Primary hyperaldosteronism Plasma aldosterone: Renin ratio [10] investigations warrants a renal ultrasound scan. It is also Thyroid disease Thyroid function tests advisable to order serum sodium, potassium and glucose because Pheochromocytoma 24‑hour urinary catecholamine level the test is simple and often helpful. Because of the confounding Plasma metanephrines Cushing’s syndrome Urinary cortisol nature of the white‑coat effect, 24‑hour ambulatory blood [11,14,15] Obstructive sleep apnoea Polysomnography pressure monitoring should also be undertaken. Pressure Renovascular disease Renal artery duplex scan readings from ambulatory monitoring correlate more closely Renal parenchymal disease Renal ultrasound scan with morbidity and mortality than measurements obtained in Coarctation of the aorta Cardiac ultrasound scan [14] clinic. Journal of Family Medicine and Primary Care 194 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension smoking cessation, reduction in alcohol intake, dietary sodium Chlorthalidone has a longer half‑life and duration of action restriction, healthy eating plans, increased physical activity and than indapamide and is associated with a higher risk of renal weight loss. Lifestyle interventions complement the efficacy  of  impairment and hypokalaemia. Thus in predisposed patients drug therapy and, alone, are often satisfactory in uncomplicated such as the elderly or those with renal insufficiency  indapamide  [27] essential hypertension. might be a superior substitute. An appropriate starting dose [19] is a 1.5 mg controlled‑release tablet each morning. Patients Pharmacological treatment with severe renal impairment (GFR below 30 mls/min) should There is little randomised trial data to guide choice of drug regimen have their thiazide replaced by a loop diuretic under specialist [12] for patients with resistant hypertension and recommendations are guidance. largely empirical. In general, the best strategy is to formulate a combination therapy that targets different physiological In some cases the drug regimen may be altered by having mechanisms and accounts for patient comorbidities. patients take one antihypertensive agent at night‑time instead of conventional morning‑only dosing. Blood pressure generally The preferred initial drug choices are the same as for essential lowers physiologically during sleep and nocturnal hypertension, [18] hypertension. The guidelines of the National Institute for or so‑called ‘non‑dipping’, has been associated with poorer [28,29] Health and Clinical Excellence (NICE) recommend initial cardiovascular prognosis. There is recent trial data on resistant treatment with an angiotensin‑converting enzyme inhibitor hypertension which suggests improved blood pressure reduction (ACE inhibitor) in patients younger than 55 years of age, or a with fewer cardiovascular events if one antihypertensive is [30] dihydropyridine calcium channel blocker (CCB) in patients older ingested nocturnally. Importantly, there is no significant [19] [31] than 55 or black patients of any age. These options can then difference in adverse outcomes with this approach. Therefore, be trialled in combination and titrated as necessary before adding shifting one agent to bedtime dosing is not an unreasonable a thiazide as the third medication. decision in patents with resistant hypertension. However, if electing to trial nocturnal therapy it is generally wise to avoid a Guidelines endorse commencement of antihypertensive diuretic as the night‑time medication. treatment with only one drug because adequate monotherapy [20] controls hypertension in 30% of cases. If monotherapy Spironolactone is recommended as the fourth antihypertensive [12,32] is insufficient  the regimen could be modified  depending on  drug.  The Scandinavian Cardiac Outcomes Trial (ASCOT)  therapeutic effect by altering dose or adding an additional class showed mean blood pressure reduction of 22/10 mmHg at one of drug. Triple therapy must be optimised before selecting further year follow‑up in patients with resistant hypertension randomised [27] add‑on therapy because optimal dosing and drug selection can to receive spironolactone as the fourth medication. A general see blood pressure normalise in many patients. rule is to commence patients on 25 mg per day, which may require about 2 weeks for full effect. This dose can be increased Whatever regimen is chosen it is important that it be tailored to gradually, preferably over several months, to a maximum of the individual patient. Comorbidities must be considered when 100 mg daily if necessary. Adverse effects of spironolactone selecting an antihypertensive agent. For instance, in patients usually appear at higher doses where patients may complain of over 55 years of age with evidence of heart failure a thiazide gynecomastia and breast tenderness, menstrual irregularities and diuretic might be a more suitable first‑line  option than a CCB.  sexual dysfunction. Amiloride, a potassium‑sparing diuretic, is Alternatively, if patients are intolerant to an ACEI because of a reasonable alternative in those intolerant of spironolactone. cough it is acceptable to replace the ACEI with an angiotensin Its dose ranges from 2.5‑10 mg daily. A caveat for both receptor blocker (ARB). This should achieve a comparable blood spironolactone and amiloride is the need for careful routine pressure lowering effect. monitoring of serum potassium. If the blood potassium level exceeds 4.5 mmol/L intensification  of thiazide therapy should  [33] Most patients with hypertension are prescribed be considered. hydrochlorothiazide as the diuretic of choice. However, several recent clinical trials have demonstrated superior blood pressure The dual renal‑angiotensin‑aldosterone system blockade offered reduction with chlorthalidone, especially in patients with resistant by spironolactone with ACEIs is not matched by combining [20‑24] hypertension. Chlorthalidone is a thiazide‑like diuretic with ACEIs with ARBs. The landmark Ongoing Telmisartan  a longer half‑life and greater potency than hydrochlorothiazide. Alone and in combination with Ramipril Global Endpoint A good initial step in controlling refractory hypertension Trial (ONTARGET) demonstrated no additional benefit  between  [34] is therefore to switch patients from hydrochlorothiazide to using ACEIs or ARBs alone and in combination. Treatment chlorthalidone. The starting dose of chlorthalidone is 12.5 mg regimens therefore should not include both an ACEI and ARB daily, taken in the morning, titrated if necessary to a maximum simultaneously. [25,26] of 50 mg daily. Difficult  patients will require referral to a hypertension specialist.  Indapamide is an alternative thiazide‑like agent which may Indications for referral include patients with uncontrolled be more suitable than chlorthalidone in some patients. blood pressure despite receiving maximum tolerated doses of Journal of Family Medicine and Primary Care 195 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension four medications, patients suffering end‑organ damage as a or poor glycaemic control, traditional beta blockers like atenolol consequence of their high blood pressure, or patients with a or metoprolol may instead be indicated. Their antihypertensive suspected secondary cause [Table 4]. All patients unresponsive benefit  is presumably smaller although head‑to‑head comparison  [12] to quadruple therapy should be revaluated for a secondary cause. data is lacking. Most patients with resistant hypertension do achieve blood Other options include alpha blockers, clonidine, methyldopa and  pressure control through pharmacotherapy provided they direct vasodilators such as hydralazine or minoxidil. These seldom [35] are properly evaluated and treated. Patients who remain form part of the routine management of hypertension and hypertensive despite four agents can have additional medications should be prescribed with expert advice. Although such agents trialled sequentially with direction from a specialist [Figure 1]. are very efficacious  in controlling blood pressure their use must  Drug selection must be stepwise with careful appraisal of clinical be tempered by side effect profiles  and the comorbidities of the  circumstances at each stage. Patient comorbidities often dictate patient [Table 5]. These medications have not been adequately medication choices and it is judicious to begin each medication studied in resistant hypertension and the choice of agent depends at the lowest dose practicable. Occasionally these less‑frequently  largely on patient situation and individual prescriber preference. used agents will require earlier introduction depending on clinical Most clinicians tend to opt for centrally‑acting agents before circumstances. the direct vasodilator drugs because experience with their use is wider. Vasodilating beta blockers, such as carvedilol and labetalol, [12] are a preferable next option as fifth‑line drug therapy. Interventional treatment They are not recommended as first‑line  therapy for patients  There is a need for alternative treatment strategies in refractory with uncomplicated hypertension because they offer less patients who remain hypertensive despite optimum medical cardiovascular protection than other agents. For example, patients therapy. Two potentially effective interventional therapies treated with beta blockers in the Controlled ONset Verapamil  are currently being assessed for this purpose. These are renal INvestigation of Cardiovascular Endpoints (CONVINCE) trial  denervation and carotid sinus stimulation. had higher rates of stroke than with any of CCBs, ACEIs or [36] thiazides. Carvedilol should be initiated at 12.5 mg daily for at Renal denervation (RD) is a minimally invasive percutaneous least two days, before increasing by 12.5 mg every two weeks to a approach that involves placement of an electrode in the renal maximum dose of 50 mg per day. Labetalol is commenced initially arteries followed by ablation of sympathetic nerves. Sympathetic at 100 mg twice daily and titrated to a maximum of 2.4 g daily. innervation stimulates renin release from the juxtoglomerular Labetalol must not be increased faster than by 200 mg increments apparatus and afferent vasoconstriction of renal vessels, both per day. In some patients such as those with ischemic heart disease of which lead to increased tubular reabsorption of sodium and elevated blood pressure. Renal denervation is therefore based Table 4: Indications for specialist referral in on the principle that deactivation of renal sympathetic nerves [9] hypertensive patients will curb hypertension. Suspected secondary hypertension Hypertension with target‑organ damage Until recently, available data indicated that this procedure eGFR <30ml/min/1.73m provides moderate blood pressure reduction in patients with eGFR decline of 15% within 3 months resistant hypertension. This was demonstrated in several Proteinuria >1g/day unblinded studies, including SYMPLICITY‑HTN‑2. That trial, Requiring >4 medications for pressure control [10,40] conducted in centres across Australia, New Zealand and Europe, [25,32,37‑40] Table 5: Specialised medication options for resistant hypertension Drug class Examples Recommended dose Notes Alpha Prazosin 0.5 mg daily, initially nocte, Useful option in men with benign prostatic hyperplasia and lower urinary tract symptoms blockers increasing to maintenance Can cause postural hypotension so use with caution in elderly dose of 1‑10 mg twice daily Centrally Clonidine 50 mcg twice daily, up to Adverse effects are relatively common with both agents, such as dry mouth and sedation acting 300 mcg twice daily Abrupt cessation of clonidine can cause severe rebound hypertension so must be weaned carefully sympatholytic Methyldopa 125 mg twice daily initially, Methyldopa is a safe non‑teratogenic option in pregnancy and remains widely used in that up to 250 mg twice daily setting Direct Minoxidil 5 mg daily, up to 30 mg Minoxidil commonly causes reflex tachycardia and fluid retention vasodilators twice daily Minoxidil must be used cautiously in patients with heart failure and coronary artery disease Hydralazine 12.5 mg daily, up to 200 mg Minoxidil requires co‑administration of a beta blocker and loop diuretic to offset tachycardia daily in divided doses and fluid retention Minoxidil causes hypertrichosis so should be avoided in women Hydralazine provides less antihypertensive effect but is also associated with fewer adverse effects Most clinicians familiar with their use elect hydralazine in women and minoxidil in men Journal of Family Medicine and Primary Care 196 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension Figure 1: Stepwise pharmacologic management of resistant hypertension demonstrated a mean pressure reduction of 32/11 mmHg at Experience with carotid sinus stimulation is currently limited. six months post‑RD, and was not associated with any major Knowledge of device safety and long‑term efficacy  remains  [41] complications. insufficient  and it is not a routinely available management option  at this time. However, a blinded randomised controlled trial released in April 2014, SYMPLICITY‑HTN‑3, failed to demonstrate any Conclusion blood pressure benefit  for RD versus a sham control procedure  [42] Hypertension is a challenging clinical problem with a significant  in 535 patients with resistant hypertension. This paper represents the most definitive  evidence available to date, in  proportion of patients failing to achieve blood pressure control contradiction to past studies, and therefore the utility of RD despite extensive medical therapy. Resistant hypertension is remains unestablished. defined  as blood pressure that remains above 140/90 mmHg  despite optimal use of three antihypertensive medications The other emerging intervention is carotid sinus stimulation. This of different classes, including a diuretic. Such patients are is founded on the theory that continuous electrical stimulation more likely to have a secondary cause and to suffer end‑organ of carotid baroreceptors, via an implantable device, should damage. Most individuals with resistant hypertension will inhibit sympathetic output. Carotid baroreefl x  activation is a new  achieve normotension with conscientious treatment decisions. procedure with limited experience. Although several feasibility Patients must be approached in a stepwise manner beginning studies have demonstrated appreciable pressure reduction the with traditional antihypertensive therapy followed gradually by safety of this technique is not yet certain. additional agents to reach a quadruple or five‑drug  compound  regimen if necessary. In those who remain hypertensive despite The Rheos Pivotal Trial is the only major double‑blind thorough medical management, there are interventional options randomised study published on carotid sinus stimulation. It currently under development which are promising but require reported substantial blood pressure reduction but was also further research. associated with serious procedure‑related adverse effects in [43] 25.2% of participants. Complications were primarily related Acknowledgement to nerve injury during device implantation though there was also a 2.3% incidence of hypertension‑induced stroke. This event We are grateful to Dr Suku Thambar for his valuable feedback on earlier rate exceeds procedural safety allowances and is unsatisfactory. drafts of this paper. Journal of Family Medicine and Primary Care 197 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension in adults. London: National Institute for Health and Clinical References Excellence; 2011. 1. Australian Institute of Health and Welfare. High Blood 20. Frank J. Managing hypertension using combination therapy. Pressure [internet]. 2013 [updated 2013 Sep 18; cited Am Fam Phys 2008;77:1279‑86. 2014 Jan 14]. 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Hydrochlorothiazide versus blood pressure in adults; Report from the panel members chlorthalidone: Evidence supporting their interchangeability. appointed to the eighth joint national committee (JNC 8). Hypertension 2004;43:4. JAMA 2014;311:507‑20. th 25. Monthly Index of Medical Specialties. 50 ed. Sydney: MIMS 5. Pimenta E, Calhoun D. Treatment of resistant hypertension. Australia; 2013. Chlorthalidone; p. 57. J Hypertension 2010;28:2194‑5. 26. eTG complete. 2015. Available from: www.online.tg.org.au 6. Briganti E, McNeil J, Shaw J, Zimmet P, Chadban S, Atkins R, [Last updated on 2012 Oct 01; cited on 2014 Feb 15] et al. Untreated hypertension among Australian adults: The 27. Madkour H, Gadallah M, Riveline B, Plante GE, Massry SG. 1999‑2000 Australian diabetes, obesity and lifestyle study. Indapamide is superior to thiazide in the preservation Med J Aust 2003;179:135‑9. of renal function in patients with renal insufficiency and 7. Australian Bureau of Statistics. 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Journal of Family Medicine and Primary Care 198 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension 39. Gottlieb T, Katz F, Chidsey C. Combined therapy with resistant hypertension. N Engl J Med 2014;370:1393‑401. vasodilator drugs and beta‑adrenergic blockade in 43. Bisognano J, Bakris G, Nadim M, Sanchez L, Kroon A, hypertension: A comparative study of minoxidil and Schafer J, et al. Baroreflex activation therapy lowers blood hydralazine. Circulation 1972; 45: 571‑82. pressure in patients with resistant hypertension; results 40. Australian Medicines Handbook. Adelaide: Pharmaceutical from the double blind, randomised, placebo‑controlled Society of Australia; 2010. Rheos Pivotal Trial. J Am Coll Cardiol 2011;58:765‑73. 41. Esler M, Krum H, Sobotka P, Schlaich M, Schmeider R, Boehm M, et al. Renal sympathetic denervation in patients with treatment‑resistant hypertension (The How to cite this article: Yaxley JP, Thambar SV. Resistant hypertension: SymplicityHTN‑2 Trial): A randomised controlled trial. An approach to management in primary care. J Fam Med Primary Care Lancet 2010;376:1903‑09. 2015;4:193-9. 42. Bhatt D, Kandzari D, O’Neil W, D’Agostino R, Flack J, Source of Support: Nil. Conflict of Interest: None declared. Katzen B, et al. A controlled trial of renal denervation for Journal of Family Medicine and Primary Care 199 April 2015 : Volume 4 : Issue 2 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Family Medicine and Primary Care Pubmed Central

Resistant hypertension: an approach to management in primary care

Yaxley, Julian P.; Thambar, Sam V.
Journal of Family Medicine and Primary Care , Volume 4 (2) – Nov 1, 168
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Family Practice Resistant hypertension: an approach to management in primary care 1 2 Julian P. Yaxley , Sam V. Thambar 1 2 Department of Medicine, Redcliffe Hospital, Department of Medicine, Gold Coast University Hospital, Queensland, Australia A b s t r Ac t Hypertension is widely encountered in family medicine. Despite its prevalence, many patients have uncontrolled or difficult‑to‑control blood pressure. Resistant hypertension is defined as hypertension that is poorly responsive to treatment and requires the use of multiple medications to achieve acceptable blood pressure ranges. It may be a consequence of secondary hypertension or have no identifiable cause. Resistant hypertension is important to recognise because it places patients at risk of end‑organ damage. Primary care physicians should be aware of the therapeutic approach for hypertension when traditional therapy fails. This article aims to familiarise readers with the evaluation and management of resistant hypertension by outlining the most recent evidence‑based treatment options. Keywords: Blood pressure, cardiovascular disease, renal denervation, resistant hypertension [6,7] of whom are poorly controlled. Its prevalence is likely to Introduction [8] continue rising. Hypertension is defined  as persons 18 years of age and over  with a systolic pressure reading of 140 mmHg or more or It is estimated that approximately 10% of hypertensive patients [9,10] a diastolic reading of 90 mmHg or more, or those taking in westernised countries have resistant hypertension. Doctors [1,2] antihypertensive medications. Between 90‑95% of cases in primary care can expect to encounter resistant hypertension are essential hypertension in which there is no identifiable   one in every 20 hypertensive patients, compared with higher [3] [10] cause. The remaining cases of hypertension are secondary to a rates in specialist clinics. distinguishable process and would likely resolve if the underlying condition was treated. Aetiology and pathogenesis In most cases the pathogenesis of resistant hypertension is A considerable number of patients fail to reach target blood uncertain. Only in a minority of instances is the problem due  pressure ranges despite lifestyle advice and standard medical to secondary hypertension. In the absence of a secondary therapy. Resistant hypertension is defined  as blood pressure  cause the condition is most likely multifactorial. Proposed that remains above 140/90 mmHg despite use of three mechanisms include genetic factors, aberrant sympathetic antihypertensive medications of different classes at the best nervous system activation and altered renal sodium and water [4,5] tolerated doses, one of which must be a diuretic. handling due to changes in the renin‑angiotensin‑aldosterone system. Epidemiology Hypertension is widely encountered in primary care and is the Clinical features and diagnosis [1] most common condition managed at primary care level. It Although hypertension is usually asymptomatic detection and [2] accounts for 8.6% of all visits to a primary care physician. treatment remains important. Uncontrolled blood pressure is a Hypertension affects 32% of adults in western society, two‑thirds considerable cardiovascular risk factor that makes target‑organ [11] damage more likely. Possible end‑organ consequences of Access this article online untreated hypertension include heart failure, stroke, ischemic Quick Response Code: Website: heart disease and renal failure. www.jfmpc.com Address for correspondence: Dr. Julian P. Yaxley, Department of Medicine, Redcliffe Hospital, DOI: 10.4103/2249-4863.154630 Queensland, Australia. E‑mail: [email protected] Journal of Family Medicine and Primary Care 193 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension Resistant hypertension presents in patients who have persistently Further screening investigations for secondary causes are elevated blood pressure which responds minimally to therapy. not compulsory. Additional tests [Table 3] should be chosen Approximately six months of treatment with three conventional depending on the clinical circumstances of the patient as revealed antihypertensive agents should be allowed for at least some blood by history and examination. [9] pressure correction. If at six months treatment is proving Finally, all patients with ongoing uncontrolled hypertension unsuccessful the possibility of resistant hypertension may be should be assessed routinely for any signs of end‑organ contemplated. compromise. This may include measures such as yearly fundoscopy, electrocardiogram and urine dipstick. The true prevalence of resistant hypertension is difficult  to  quantify because many patients actually suffer ‘pseudo‑resistant’ hypertension. Pseudo‑resistant hypertension refers to poorly Management controlled disease which appears resistant but is actually Primary care physicians are familiar with the management of attributable to other factors. The commonest reasons for essential hypertension. Treatment should comprise both lifestyle apparent treatment resistance are medication non‑compliance modification  and pharmacologic therapy. The blood pressure  and insufficient  drug therapy. Other implicated factors include  goal in uncomplicated patients is 140/90 mmHg which could [17] failure to adhere to lifestyle advice, poor measurement technique, be relaxed to 150/90 in patients greater than 60 years of age. whitec ‑ oat hypertension and the use of medications that interfere A more appropriate treatment target in patients with end‑organ [5,15] with blood pressure [Table 1]. damage is 130/80 mmHg. A key step in diagnosing resistant hypertension is confirming  Non‑pharmacological treatment that blood pressure elevation is truly resistant. Pseudo‑resistance Non‑pharmacologic measures should be introduced in patients must be ruled out with a thorough history and medication with hypertension of any severity. Recommendations include review, followed by measurement of blood pressure with proper technique. Provided these confounders are absent and standard Table 1: Drugs that interfere with blood drug therapy has failed, resistant hypertension is diagnosed. [10] pressure control Non‑steroidal anti‑inflammatories Every patient with resistant hypertension requires at least some Oral contraceptives screening for secondary causes [Table 2]. Obstructive sleep  Corticosteroids apnoea, chronic kidney disease and primary hyperaldosteronism Tricyclic antidepressants [12] are the most frequent comorbidities. Although secondary Monoamine oxidase inhibitors hypertension is more likely in resistant hypertension than in Other substances‑caffeine, cocaine, alcohol patients whose blood pressure is controlled, most still do not [13] have an identifiable cause. [10] Table 2: Causes of secondary hypertension Evaluation for secondary causes should include comprehensive Chronic kidney disease Renovascular disease history and physical examination searching for any clues pointing Obstructive sleep apnoea towards to an underlying diagnosis. For example the patient may Coarcation of the aorta have symptoms of obstructive sleep apnoea, or alternatively Pheochromocytoma episodic palpitations with headaches and diaphoresis might Primary hyperaldosteronism suggest pheochromocytoma, while an abdominal bruit could Cushing’s syndrome indicate renal artery stenosis. Oftentimes however, the clinical  Thyroid disease assessment will be unremarkable. Intracranial mass Beyond history and examination, all patients with resistant hypertension should be investigated at minimum with a serum Table 3: Initial investigations for suspected causes of [10,16] creatinine test, estimated glomerular filtration  rate and urine  secondary hypertension [10] dipstick. This is due to the high prevalence of chronic kidney Disorder Suggested investigation disease in this population. Any derangement in these baseline Primary hyperaldosteronism Plasma aldosterone: Renin ratio [10] investigations warrants a renal ultrasound scan. It is also Thyroid disease Thyroid function tests advisable to order serum sodium, potassium and glucose because Pheochromocytoma 24‑hour urinary catecholamine level the test is simple and often helpful. Because of the confounding Plasma metanephrines Cushing’s syndrome Urinary cortisol nature of the white‑coat effect, 24‑hour ambulatory blood [11,14,15] Obstructive sleep apnoea Polysomnography pressure monitoring should also be undertaken. Pressure Renovascular disease Renal artery duplex scan readings from ambulatory monitoring correlate more closely Renal parenchymal disease Renal ultrasound scan with morbidity and mortality than measurements obtained in Coarctation of the aorta Cardiac ultrasound scan [14] clinic. Journal of Family Medicine and Primary Care 194 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension smoking cessation, reduction in alcohol intake, dietary sodium Chlorthalidone has a longer half‑life and duration of action restriction, healthy eating plans, increased physical activity and than indapamide and is associated with a higher risk of renal weight loss. Lifestyle interventions complement the efficacy  of  impairment and hypokalaemia. Thus in predisposed patients drug therapy and, alone, are often satisfactory in uncomplicated such as the elderly or those with renal insufficiency  indapamide  [27] essential hypertension. might be a superior substitute. An appropriate starting dose [19] is a 1.5 mg controlled‑release tablet each morning. Patients Pharmacological treatment with severe renal impairment (GFR below 30 mls/min) should There is little randomised trial data to guide choice of drug regimen have their thiazide replaced by a loop diuretic under specialist [12] for patients with resistant hypertension and recommendations are guidance. largely empirical. In general, the best strategy is to formulate a combination therapy that targets different physiological In some cases the drug regimen may be altered by having mechanisms and accounts for patient comorbidities. patients take one antihypertensive agent at night‑time instead of conventional morning‑only dosing. Blood pressure generally The preferred initial drug choices are the same as for essential lowers physiologically during sleep and nocturnal hypertension, [18] hypertension. The guidelines of the National Institute for or so‑called ‘non‑dipping’, has been associated with poorer [28,29] Health and Clinical Excellence (NICE) recommend initial cardiovascular prognosis. There is recent trial data on resistant treatment with an angiotensin‑converting enzyme inhibitor hypertension which suggests improved blood pressure reduction (ACE inhibitor) in patients younger than 55 years of age, or a with fewer cardiovascular events if one antihypertensive is [30] dihydropyridine calcium channel blocker (CCB) in patients older ingested nocturnally. Importantly, there is no significant [19] [31] than 55 or black patients of any age. These options can then difference in adverse outcomes with this approach. Therefore, be trialled in combination and titrated as necessary before adding shifting one agent to bedtime dosing is not an unreasonable a thiazide as the third medication. decision in patents with resistant hypertension. However, if electing to trial nocturnal therapy it is generally wise to avoid a Guidelines endorse commencement of antihypertensive diuretic as the night‑time medication. treatment with only one drug because adequate monotherapy [20] controls hypertension in 30% of cases. If monotherapy Spironolactone is recommended as the fourth antihypertensive [12,32] is insufficient  the regimen could be modified  depending on  drug.  The Scandinavian Cardiac Outcomes Trial (ASCOT)  therapeutic effect by altering dose or adding an additional class showed mean blood pressure reduction of 22/10 mmHg at one of drug. Triple therapy must be optimised before selecting further year follow‑up in patients with resistant hypertension randomised [27] add‑on therapy because optimal dosing and drug selection can to receive spironolactone as the fourth medication. A general see blood pressure normalise in many patients. rule is to commence patients on 25 mg per day, which may require about 2 weeks for full effect. This dose can be increased Whatever regimen is chosen it is important that it be tailored to gradually, preferably over several months, to a maximum of the individual patient. Comorbidities must be considered when 100 mg daily if necessary. Adverse effects of spironolactone selecting an antihypertensive agent. For instance, in patients usually appear at higher doses where patients may complain of over 55 years of age with evidence of heart failure a thiazide gynecomastia and breast tenderness, menstrual irregularities and diuretic might be a more suitable first‑line  option than a CCB.  sexual dysfunction. Amiloride, a potassium‑sparing diuretic, is Alternatively, if patients are intolerant to an ACEI because of a reasonable alternative in those intolerant of spironolactone. cough it is acceptable to replace the ACEI with an angiotensin Its dose ranges from 2.5‑10 mg daily. A caveat for both receptor blocker (ARB). This should achieve a comparable blood spironolactone and amiloride is the need for careful routine pressure lowering effect. monitoring of serum potassium. If the blood potassium level exceeds 4.5 mmol/L intensification  of thiazide therapy should  [33] Most patients with hypertension are prescribed be considered. hydrochlorothiazide as the diuretic of choice. However, several recent clinical trials have demonstrated superior blood pressure The dual renal‑angiotensin‑aldosterone system blockade offered reduction with chlorthalidone, especially in patients with resistant by spironolactone with ACEIs is not matched by combining [20‑24] hypertension. Chlorthalidone is a thiazide‑like diuretic with ACEIs with ARBs. The landmark Ongoing Telmisartan  a longer half‑life and greater potency than hydrochlorothiazide. Alone and in combination with Ramipril Global Endpoint A good initial step in controlling refractory hypertension Trial (ONTARGET) demonstrated no additional benefit  between  [34] is therefore to switch patients from hydrochlorothiazide to using ACEIs or ARBs alone and in combination. Treatment chlorthalidone. The starting dose of chlorthalidone is 12.5 mg regimens therefore should not include both an ACEI and ARB daily, taken in the morning, titrated if necessary to a maximum simultaneously. [25,26] of 50 mg daily. Difficult  patients will require referral to a hypertension specialist.  Indapamide is an alternative thiazide‑like agent which may Indications for referral include patients with uncontrolled be more suitable than chlorthalidone in some patients. blood pressure despite receiving maximum tolerated doses of Journal of Family Medicine and Primary Care 195 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension four medications, patients suffering end‑organ damage as a or poor glycaemic control, traditional beta blockers like atenolol consequence of their high blood pressure, or patients with a or metoprolol may instead be indicated. Their antihypertensive suspected secondary cause [Table 4]. All patients unresponsive benefit  is presumably smaller although head‑to‑head comparison  [12] to quadruple therapy should be revaluated for a secondary cause. data is lacking. Most patients with resistant hypertension do achieve blood Other options include alpha blockers, clonidine, methyldopa and  pressure control through pharmacotherapy provided they direct vasodilators such as hydralazine or minoxidil. These seldom [35] are properly evaluated and treated. Patients who remain form part of the routine management of hypertension and hypertensive despite four agents can have additional medications should be prescribed with expert advice. Although such agents trialled sequentially with direction from a specialist [Figure 1]. are very efficacious  in controlling blood pressure their use must  Drug selection must be stepwise with careful appraisal of clinical be tempered by side effect profiles  and the comorbidities of the  circumstances at each stage. Patient comorbidities often dictate patient [Table 5]. These medications have not been adequately medication choices and it is judicious to begin each medication studied in resistant hypertension and the choice of agent depends at the lowest dose practicable. Occasionally these less‑frequently  largely on patient situation and individual prescriber preference. used agents will require earlier introduction depending on clinical Most clinicians tend to opt for centrally‑acting agents before circumstances. the direct vasodilator drugs because experience with their use is wider. Vasodilating beta blockers, such as carvedilol and labetalol, [12] are a preferable next option as fifth‑line drug therapy. Interventional treatment They are not recommended as first‑line  therapy for patients  There is a need for alternative treatment strategies in refractory with uncomplicated hypertension because they offer less patients who remain hypertensive despite optimum medical cardiovascular protection than other agents. For example, patients therapy. Two potentially effective interventional therapies treated with beta blockers in the Controlled ONset Verapamil  are currently being assessed for this purpose. These are renal INvestigation of Cardiovascular Endpoints (CONVINCE) trial  denervation and carotid sinus stimulation. had higher rates of stroke than with any of CCBs, ACEIs or [36] thiazides. Carvedilol should be initiated at 12.5 mg daily for at Renal denervation (RD) is a minimally invasive percutaneous least two days, before increasing by 12.5 mg every two weeks to a approach that involves placement of an electrode in the renal maximum dose of 50 mg per day. Labetalol is commenced initially arteries followed by ablation of sympathetic nerves. Sympathetic at 100 mg twice daily and titrated to a maximum of 2.4 g daily. innervation stimulates renin release from the juxtoglomerular Labetalol must not be increased faster than by 200 mg increments apparatus and afferent vasoconstriction of renal vessels, both per day. In some patients such as those with ischemic heart disease of which lead to increased tubular reabsorption of sodium and elevated blood pressure. Renal denervation is therefore based Table 4: Indications for specialist referral in on the principle that deactivation of renal sympathetic nerves [9] hypertensive patients will curb hypertension. Suspected secondary hypertension Hypertension with target‑organ damage Until recently, available data indicated that this procedure eGFR <30ml/min/1.73m provides moderate blood pressure reduction in patients with eGFR decline of 15% within 3 months resistant hypertension. This was demonstrated in several Proteinuria >1g/day unblinded studies, including SYMPLICITY‑HTN‑2. That trial, Requiring >4 medications for pressure control [10,40] conducted in centres across Australia, New Zealand and Europe, [25,32,37‑40] Table 5: Specialised medication options for resistant hypertension Drug class Examples Recommended dose Notes Alpha Prazosin 0.5 mg daily, initially nocte, Useful option in men with benign prostatic hyperplasia and lower urinary tract symptoms blockers increasing to maintenance Can cause postural hypotension so use with caution in elderly dose of 1‑10 mg twice daily Centrally Clonidine 50 mcg twice daily, up to Adverse effects are relatively common with both agents, such as dry mouth and sedation acting 300 mcg twice daily Abrupt cessation of clonidine can cause severe rebound hypertension so must be weaned carefully sympatholytic Methyldopa 125 mg twice daily initially, Methyldopa is a safe non‑teratogenic option in pregnancy and remains widely used in that up to 250 mg twice daily setting Direct Minoxidil 5 mg daily, up to 30 mg Minoxidil commonly causes reflex tachycardia and fluid retention vasodilators twice daily Minoxidil must be used cautiously in patients with heart failure and coronary artery disease Hydralazine 12.5 mg daily, up to 200 mg Minoxidil requires co‑administration of a beta blocker and loop diuretic to offset tachycardia daily in divided doses and fluid retention Minoxidil causes hypertrichosis so should be avoided in women Hydralazine provides less antihypertensive effect but is also associated with fewer adverse effects Most clinicians familiar with their use elect hydralazine in women and minoxidil in men Journal of Family Medicine and Primary Care 196 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension Figure 1: Stepwise pharmacologic management of resistant hypertension demonstrated a mean pressure reduction of 32/11 mmHg at Experience with carotid sinus stimulation is currently limited. six months post‑RD, and was not associated with any major Knowledge of device safety and long‑term efficacy  remains  [41] complications. insufficient  and it is not a routinely available management option  at this time. However, a blinded randomised controlled trial released in April 2014, SYMPLICITY‑HTN‑3, failed to demonstrate any Conclusion blood pressure benefit  for RD versus a sham control procedure  [42] Hypertension is a challenging clinical problem with a significant  in 535 patients with resistant hypertension. This paper represents the most definitive  evidence available to date, in  proportion of patients failing to achieve blood pressure control contradiction to past studies, and therefore the utility of RD despite extensive medical therapy. Resistant hypertension is remains unestablished. defined  as blood pressure that remains above 140/90 mmHg  despite optimal use of three antihypertensive medications The other emerging intervention is carotid sinus stimulation. This of different classes, including a diuretic. Such patients are is founded on the theory that continuous electrical stimulation more likely to have a secondary cause and to suffer end‑organ of carotid baroreceptors, via an implantable device, should damage. Most individuals with resistant hypertension will inhibit sympathetic output. Carotid baroreefl x  activation is a new  achieve normotension with conscientious treatment decisions. procedure with limited experience. Although several feasibility Patients must be approached in a stepwise manner beginning studies have demonstrated appreciable pressure reduction the with traditional antihypertensive therapy followed gradually by safety of this technique is not yet certain. additional agents to reach a quadruple or five‑drug  compound  regimen if necessary. In those who remain hypertensive despite The Rheos Pivotal Trial is the only major double‑blind thorough medical management, there are interventional options randomised study published on carotid sinus stimulation. It currently under development which are promising but require reported substantial blood pressure reduction but was also further research. associated with serious procedure‑related adverse effects in [43] 25.2% of participants. Complications were primarily related Acknowledgement to nerve injury during device implantation though there was also a 2.3% incidence of hypertension‑induced stroke. This event We are grateful to Dr Suku Thambar for his valuable feedback on earlier rate exceeds procedural safety allowances and is unsatisfactory. drafts of this paper. Journal of Family Medicine and Primary Care 197 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension in adults. London: National Institute for Health and Clinical References Excellence; 2011. 1. Australian Institute of Health and Welfare. High Blood 20. Frank J. Managing hypertension using combination therapy. Pressure [internet]. 2013 [updated 2013 Sep 18; cited Am Fam Phys 2008;77:1279‑86. 2014 Jan 14]. 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Journal of Family Medicine and Primary Care 198 April 2015 : Volume 4 : Issue 2 Yaxley and Thambar: Resistant hypertension 39. Gottlieb T, Katz F, Chidsey C. Combined therapy with resistant hypertension. N Engl J Med 2014;370:1393‑401. vasodilator drugs and beta‑adrenergic blockade in 43. Bisognano J, Bakris G, Nadim M, Sanchez L, Kroon A, hypertension: A comparative study of minoxidil and Schafer J, et al. Baroreflex activation therapy lowers blood hydralazine. Circulation 1972; 45: 571‑82. pressure in patients with resistant hypertension; results 40. Australian Medicines Handbook. Adelaide: Pharmaceutical from the double blind, randomised, placebo‑controlled Society of Australia; 2010. Rheos Pivotal Trial. J Am Coll Cardiol 2011;58:765‑73. 41. Esler M, Krum H, Sobotka P, Schlaich M, Schmeider R, Boehm M, et al. Renal sympathetic denervation in patients with treatment‑resistant hypertension (The How to cite this article: Yaxley JP, Thambar SV. Resistant hypertension: SymplicityHTN‑2 Trial): A randomised controlled trial. An approach to management in primary care. J Fam Med Primary Care Lancet 2010;376:1903‑09. 2015;4:193-9. 42. Bhatt D, Kandzari D, O’Neil W, D’Agostino R, Flack J, Source of Support: Nil. Conflict of Interest: None declared. Katzen B, et al. A controlled trial of renal denervation for Journal of Family Medicine and Primary Care 199 April 2015 : Volume 4 : Issue 2

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