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Clinical Review
When optimal BP control
is difficult to achieve
Hong Kuan Kok and Alice Stanton present two case studies to illustrate
common challenges faced by GPs in the management of hypertension
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.
Case 1 – 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?
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
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Clinical Review
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.
Case 2 – 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 50s. 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 underling
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
Key points
• Essential hypertension accounts for the vast majority
(90-95%) of hypertensive patients encountered in
clinical practice.
• Screening for secondary causes of hypertension (5%)
should be considered in young patients with no risk
factors for hypertension.
• Treatment-resistant hypertension is defined as the failure to control BP despite three or more antihypertensive
agents, including a diuretic.
• The addition of aldosterone antagonists as a third or
fourth line agent is supported by recent guidelines from
the ESH and AHA and observations from ASCOT.
• Overall cardiovascular risk assessment and reduction
must not be overlooked in patients with treatment resistant hypertension.
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.
Hong Kuan Kok is honorary clinical fellow and Alice Stanton
is associate professor at the Department of Molecular and
Cellular Therapeutics, Royal College of Surgeons, Dublin
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): 18281834.
8. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? Jama, 2002. 287(11): 1427-34.
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