The vast majority of hypertensive patients suffer from essential hypertension (90-95%) in which elevation of blood pressure (BP) occurs with no clear cause. A smaller proportion of cases (5%) occur secondary to an underlying pathology. Most cases of hypertension can be readily diagnosed and managed at primary care level. 

However, it is not uncommon for the general practitioner to encounter patients in which optimal BP control is difficult to achieve or where specialist referral is warranted for further investigation and management. We present two cases to illustrate common challenges faced in the management of hypertension in a primary care setting.

Treatment-resistant hypertension

A 52-year-old male smoker with a strong family history of cardiovascular disease was diagnosed six months ago in a primary care practice with hypertension on the basis of elevated BP readings of 172/108mmHg on separate visits. Clinical examination reveals a BMI of 32kg/m2 with no evidence of target organ damage on fundoscopy or urine testing for microalbuminuria. In addition to non-pharmacological intervention such as weight loss, dietary salt and caloric restriction as well as regular physical exercise, he was started on ramipril 5mg once-daily but this failed to control his BP. Subsequently, amlodipine 5mg once-daily was added and both agents were titrated to ceiling doses. On his last visit, a thiazide diuretic, bendroflumethiazide 2.5mg was added on to his antihypertensive regimen because he failed to respond adequately. He returns for follow-up today and his 24-hour ambulatory BP monitor readings show an average day-time BP of 152/94 and night-time BP of 146/90 despite consistently saying that he has been compliant with his medications. What is the best way to proceed?

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Optimising management

This man has treatment-resistant hypertension as defined by failure to achieve optimal BP control despite three antihypertensive agents including a diuretic.¹ The 24-hour ambulatory BP monitor provides valuable information in helping to exclude spurious white coat hypertension and aids the diagnosis of refractory hypertension. Unfortunately, he is at significant risk of future cardiovascular events in view of his obesity, smoking history and family history, which makes control of cardiovascular risk factors a key priority. Lifestyle measures should be re-addressed and emphasised including dietary salt and caloric reduction, smoking cessation, avoidance of binge alcohol consumption and other concomitant regular medications should be reviewed. Our patient is also likely to have the under-diagnosed metabolic syndrome and his overall cardiovascular risk should be assessed including measurement of fasting lipid and glucose profiles to exclude co-existing hyperlipidaemia and insulin resistance. Where the history is suggestive, evaluation for obstructive sleep apnoea, which is common in overweight individuals, may identify an important contributing factor to hypertension.

Optimal BP control can be difficult to achieve in such patients and often requires a combination of three or more antihypertensive agents, titrated based on patient tolerance or the appearance of side-effects. Although evidence is limited in this area, recommendations by the European Society of Hypertension and, more recently, the American Heart Association support the addition of the aldosterone antagonist, spironolactone, at doses between 25-50mg/day in such cases.^1,2

Observations from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) support the use of spironolactone in hypertension uncontrolled by a mean of three other antihypertensive agents.³ However, the use of spironolactone, particularly in combination with angiotensin-converting enzyme or aldosterone receptor blockers can potentially cause hyperkalaemia, and careful monitoring of serum electrolytes should be performed periodically, particularly at the commencement of treatment. Peripheral alpha-adrenoreceptor blockers such as doxazosin have also been used successfully in certain patient groups, particularly where alpha-blockade is desired such as in co-existing benign prostatic obstruction. Should these measures fail, screening for secondary causes of hypertension and referral to a specialist should be considered.

Future possibilities

Newer modalities in treatment-resistant hypertension are becoming available. Selective endothelin receptor antagonists such as darusentan, which act as vasodilators, are under evaluation and have been shown to be effective as an add-on agent in this group of patients.⁴

Other invasive management options on the horizon include catheter-based renal sympathetic denervation, which has been shown to offer substantial and sustained BP reduction in a small group of patients in a multicentre proof-of-principle trial.⁵ More recently, baroreflex activation therapy with an implantable device that activates the carotid baroreflex has been shown to reduce blood pressure by a mean of 22/12mmHg with minimal side-effects.⁶ Indeed, once refined sufficiently, these novel methods hold promise for treatment-resistant hypertension and could also be invaluable options for other hypertensive patients who are not keen to remain on long-term pharmacotherapy.

Secondary hypertension

A 26-year-old female university student attends her local primary care practice for travel vaccinations and was noted to have a BP of 162/106. She is normally in good health and denies any history of anxiety attacks, palpitations or urinary tract infections in childhood. 

She takes no regular medications and her father was diagnosed with hypertension in his fifties. Clinical examination reveals equal peripheral pulses with grade 2 hypertensive retinal changes. 

A 24-hour ambulatory BP monitor was organised and confirms persistent BP elevation with a mild white coat component. She returns one week later for advice.

Hypertension in young patients aged less than 30 years is more likely to be caused by an underlying pathology, although the overall prevalence of secondary hypertension in this group still remains low. Nevertheless, the importance of identifying a potentially treatable or reversible cause of hypertension means that comprehensive screening for secondary causes should be considered in young patients under 30 with no risk factors for hypertension (eg. obesity, substance abuse) after exclusion of white coat hypertension. A systematic approach to first-line screening is helpful in excluding common causes of secondary hypertension and these predominantly involve the endocrine, renal and renovascular systems. Clinical examination may reveal a murmur or radio-femoral delay in coarctation of the aorta, the body habitus of Cushing’s syndrome, palpable kidneys in polycystic kidney disease or an audible bruit suggestive of renal artery stenosis. Significant haematuria and/or proteinuria on urine testing may suggest underlying primary renal disease.

Prior to commencement of antihypertensive therapy and referral, a number of biochemical investigations can be organised at primary care level which will help expedite diagnosis and subsequent investigations at a specialist unit. These include simple measures of urea, serum electrolytes and creatinine which may suggest underlying renal impairment. Spontaneous unprovoked hypokalaemia in a hypertensive patient should trigger a suspicion for primary hyperaldosteronism, and measurement of the plasma aldosterone to plasma renin activity ratio is an acceptable screening method for this condition, although there are limitations to this measurement as outlined in the European Society of Hypertension guidelines.^1,7

Thyroid function tests and plasma metanephrines should also be measured to exclude hypothyroidism or an underlying phaeochromocytoma, particularly where the history is suggestive of episodic headaches, palpitations, sweating and anxiety attacks. Measurement of plasma-free metanephrines have been found to be the best biochemical test for diagnosing a phaeochromocytoma as compared to plasma and urinary catecholamines or urinary metanephrines.⁸ Measures of 24-hour urinary cortisol excretion is useful as a practical investigation for Cushing’s syndrome before dexamethasone suppression testing.¹ These relatively simple and easy-to-access investigations will help pave the way for other second-line investigative modalities including specialised imaging techniques, should the initial screen prove to be negative. Following this consultation, a number of blood investigations including a renal profile was organised and she was referred on for imaging studies. 

Renal duplex ultrasonography revealed asymmetrical kidneys with evidence of unilateral renal artery stenosis. She was subsequently referred on for consideration of renal artery revascularisation. 

References 

1. Mancia G, De Backer G, Dominiczak A et al. Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension and of the European Society of Cardiology. Eur Heart J 2007; 28(12): 1462-1536
2. Calhoun DA, Jones D, Textor S et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008; 51(6): 1403-1419
3. Chapman N, Dobson J, Wilson S et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007; 49(4): 839-845
4. Weber MA, Black H, Bakris G et al. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial. Lancet 2009; 374(9699): 1423-1431
5. Krum H, Schlaich M, Whitbourn R et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009; 373(9671): 1275-1281
6. Scheffers IJ, Kroon AA, Schmidli J et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010; 56(15): 1254-1258
7. Ganguly A. Primary aldosteronism. N Engl J Med 1998; 339(25): 1828-1834
8. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? Jama, 2002. 287(11): 1427-34