Identification and prevention of ‘genuine’ resistant hypertension

Solini A, Ruilope LM
Nat Rev Cardiol. 2013 May;10(5):293-6. doi: 10.1038/nrcardio.2013.23. Opinion

Background

Resistant hypertension is defined as a blood pressure (BP) that remains above the target despite the concurrent use of three or more antihypertensive agents of different classes, including one diuretic. It is a clinical problem faced by both primary-care clinicians and specialists. Resistant hypertension is accompanied by a significant increase in the overall risk of cardiovascular and renal events.
This Perspective article will discuss the main reasons for inadequate BP control and the development of resistant hypertension and how the latter can be prevented.

Inadequate measurement of BP

Data from the Spanish ambulatory blood pressure monitoring (ABPM) Registry suggest that one third of patients has ‘white coat’ hypertension, meaning that patients only exhibit elevated BP in a clinical setting. Data from the ABPM Registry suggests that  patients diagnosed with resistant hypertension have ‘normal’ ambulatory BP. Also, up to 31% of patients taking three or more antihypertensive drugs with seemingly well-controlled BP in a clinical setting, show  at least one measurement of systolic BP > 130 mmHg or diastolic BP > 80 mmHg in a 24h period on ABPM. This is called ‘masked’ hypertension.
In order to reduce the high rate of incorrect diagnosis, patients should perform frequent home BP measurements and ABPM for 24 hours should be mandatory in patients with suspected resistant hypertension.

Clinical inertia

Failure to initiate or advance therapy for a patient who has not reached the evidence-based BP goal has been termed clinical inertia. This is often the result of a combination of factors involving patients, care providers and health systems. But the largest responsibility for the development of clinical inertia should be ascribed to the clinician. Not adhering to guidelines, overestimating the effect of treatment or underestimating the cardiovascular risk can all be detrimental.
Studies suggest that intensification of treatment is not consistently applied in patients with elevated BP. Continuous training that highlights the importance of reaching BP < 140/90 mmHg  is important. Also, other pragmatic measures could be used in a primary care setting to reduce clinical inertia, for example keeping a hypertension registry to record individual BP targets and organising period recall of patients.

Poor compliance to medication

European and American guidelines indicate that daily compliance and long-term adherence to therapy are the most important objectives In the treatment of  arterial hypertension. Patients with hypertension tend to take only part of their prescribed medication. Conditions can remain clinically silent for years, which may make the patient feel that medication is not needed. Many other reasons, including socio-economic and personal factors can cause patients to be less inclined to take their medications.
Improvements in the organisation of the health system and communication can help to improve the quality of care, and patient compliance.

Inadequate drug treatment

Arterial hypertension is generally initially treatment with a combination of two antihypertensive drugs, in an attempt to control BP in three months. Resistant hypertension develops in 2% of patients receiving such treatment. Some patients will have genuine resistant hypertension, others may merely need a different combination of drugs.
A diuretic agent should be considered for each hypertensive patients who requires three or more drugs for BP control. Spironolactone has been shown to be particularly effective in controlling resistant hypertension, possibly because these patients often have primary hyperaldosteronism (ASPIRANT trial). Eplerenone can also be used if patients cannot tolerate spironolactone, but has a lower efficacy. Another strategy can be to add a calcium antagonist to a regimen including a renin-angiotensin system blocker, a diuretic and a calcium-channel blocker could be added to an extended release nifedipine.

Salt intake and dietary habits

Excessive sodium intake is a modifiable cause of resistant hypertension. Reduction of dietary sodium can yield reductions of systolic and diastolic BP as well as the incidence of coronary heart disease, stroke, myocardial infarction and all-cause mortality. A low-salt diet could be enough to render patients with resistant hypertension responsive to drug treatment.
Resistant hypertension is often seen in patients with obesity or type 2 diabetes. High fasting plasma glucose is an independent predictor of the development of resistant hypertension (ASCOT trial), although the direct link between excessive sugar or fat intake on the development of resistant hypertension is unknown.

Underlying causes

Primary aldosteronism
Excessive release of the hormone aldosterone by the adrenal cortex characterises primary aldosteronism. Through increasing sodium and water retention, it may cause hypertension. Therefore, it should be excluded as part of the diagnosis of resistant hypertension. Symptoms are not specific, thus diagnosis can be difficult. Hypertension combined with a spontaneous hypokalemia or the development of severe or persistent hypokalemia despite treatment with low-to-moderate doses of potassium-wasting diuretics can be an indication to consider aldosteronism, although a large part of patients with aldosteronism are normokalemic. The aldosterone:renin ratio can be quantified to help diagnosis, although some anti-hypertensive drugs can perturb this ratio.

Obstructive sleep apnoea (OSA)
OSA is common among patients with resistant hypertension. If patients with poorly controlled BP report snoring, witnessed apnoea, or frequent sleepiness during the day, OSA should be investigated. Polysomnographic examination can help confirm the diagnosis, as symptoms of OSA are frequently atypical in patients with resistant hypertension.
Resistant hypertension and OSA share common risk factors. OSA may also contribute to poor BP control by increasing sympathetic tone, reduced baroreflex sensitivity, endothelial dysfunction and impaired ion metabolism.

Neurogenic hypertension
Evidence suggests involvement of the sympathetic nervous system contributes to the development of primary hypertension. For instance, renal sympathetic denervation controls BP in patients in which BP could not be controlled with three or more drugs. 

Conclusion

Clinicians and patients need to work together to correctly diagnose BP values in different settings, and to improve patient compliance. Clinical inertia needs to be prevented. A multifaceted approach will improve clinical outcome. Apparent treatment -unresponsive hypertension should be distinguished from genuine ’resistant’ hypertension. The latter should then be treated with an accurate therapeutic strategy  that includes lifestyle and dietetic changes and pharmacological treatment, and careful follow-up.

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