Diagnosis and management of hypertension in primary care
Hypertension is a major modifiable risk factor for cardiovascular disease, but conflicting opinions remain about optimal blood pressure targets. This article discusses the various definitions of hypertension, provides guidance on management in primary care and advises when referral to secondary care is needed.
Hypertension is a substantial risk factor for cardiovascular disease1 and the largest contributor to mortality worldwide.2 Despite this, controversies remain about when to start treatment and what blood pressure (BP) targets to aim for. How hypertension is defined has changed over time and varies in different parts of the world. This article highlights some of these changes and focuses on the diagnosis and treatment of hypertension in primary care, with advice on when to refer patients for investigation and management in secondary care.
In 2017, the American College of Cardiology (ACC) and American Heart Association (AHA) published new joint guidelines on the diagnosis and management of hypertension, lowering the threshold of hypertension to systolic BP ≥130mmHg or diastolic BP ≥80mmHg (see Table 1).3 Results from the SPRINT trial, a randomised controlled trial with a more intensive target systolic BP of less than 120mmHg rather than the more traditional 140mmHg target have clearly influenced this decision. This trial was stopped early after about three years, when more intensive treatment resulted in a significant reduction in the primary outcome (composite of cardiovascular events) and in all-cause mortality.4
Table 1. Comparison of the definition and staging of hypertension based on clinic blood pressure in the most recent British, American and European guidelines for the diagnosis and management of hypertension. Blood pressure measurements are in mmHg
The new definition in the USA will result in substantial increases in the number of people labelled as hypertensive, and has not been adopted in the updated joint European Society of Cardiology (ESC) and European Society of Hypertension (ESH) guidelines of 2018.5 However, the ESC/ESH 2018 guidelines do now advocate starting treatment at stage/grade 1 (ie systolic BP 140–159mmHg and/or diastolic BP 90–99mmHg), regardless of cardiovascular risk, and targeting a systolic BP of 130mmHg or less.5
In the UK, hypertension is still currently defined by the British and Irish Hypertension Society (BIHS) as clinic systolic BP ≥140mmHg and/or diastolic BP ≥90mmHg, and ambulatory systolic BP ≥135mmHg and/or diastolic BP ≥85mmHg. An update to the current NICE guideline on hypertension in adults (CG127)6 is expected in August 2019. The draft recommendations do not lower the threshold for diagnosis of hypertension but do advocate starting antihypertensive treatment at stage 1 hypertension at a lower 10-year risk of cardiovascular disease, from 20% to 10% in patients under the age of 80 years.
Perhaps not surprisingly, serious adverse events including hypotension, syncope, electrolyte abnormalities, and acute kidney injury or acute renal failure, were significantly more frequent in the intensive-treatment group than in the standard-treatment group in the SPRINT trial.4 Achieving the right balance between reducing cardiovascular morbidity and mortality and avoiding adverse events or affecting quality of life is just one of the many challenges facing clinicians treating patients with hypertension.
Excluding white-coat syndrome in primary care
White-coat syndrome is abnormally elevated BP in the medical environment and normal BP during usual daily life.7 In order to exclude it, the current NICE guideline advises offering all patients with a clinic BP of 140/90mmHg or higher an ambulatory blood pressure monitor (ABPM), or home BP monitoring. ABPM is considered the gold standard for the diagnosis of hypertension, but not all GP practices have the resources to offer it, and not all patients can tolerate it.
Rather than requesting or referring all patients for ABPM, an alternative strategy has recently been developed and validated in a research setting. It is known as the PROOF-BP calculator (see Figure 1), which is freely available online.8 This is an evidence-based tool that uses an algorithm for predicting a patient’s out-of-office BP, based on basic demographics, history of hypertension or cardiovascular disease, and three consecutive clinic BP measurements. It has been shown to have a sensitivity of 97% and specificity of 76%, with an area under the receiver operator characteristic curve (AUROC) of 0.86.9 Use of this triaging strategy would result in reduced demand for ABPM and has been shown to be cost-effective,10 but a small percentage of patients (6–10%) would receive treatment deemed not necessary had they received ABPM.9
Figure 1. PROOF-BP calculator tool: Predicting Out-of-Office Blood Pressure in the clinic. Reproduced with permission from the author James Sheppard. Available from: https://sentry.phc.ox.ac.uk/proof-bp/calc.html
Causes and risk factors
In the majority of patients with hypertension, no single cause is discernible. There is often a family history of the condition, yet monogenetic hypertensive syndromes are extremely rare. Multiple genes are therefore likely implicated and if there is a strong positive family history, the risk of developing hypertension increases nearly four-fold compared with the general population.11
Approximately 9 in 10 of the hypertensive population base will have primary or ‘essential’ hypertension. It is recommended that patients under the age of 40 years should be referred to a specialist in order to exclude secondary causes of hypertension (see Table 2). The exact prevalence of secondary hypertension is unknown although it is thought to affect between 5–15% of hypertensive patients.12 The conditions screened for by history, examination and investigation include coarctation of the aorta, renal artery stenosis (see Figure 2), fibromuscular dysplasia (a non-atherosclerotic form of renal artery stenosis), primary aldosteronism, phaeochromocytoma and paraganglioma, Cushing’s syndrome and acromegaly, as well as thyroid and intrinsic renal diseases.
Table 2. Patients who should be referred to a hypertension specialist clinic in secondary care
In order to exclude primary aldosteronism (also known as Conn’s syndrome in the context of a benign adrenal tumour, Figure 3), blood tests for renin and aldosterone are performed. A classical biochemical picture of primary aldosteronism would be suppressed or undetectable renin with high (or potentially normal) aldosterone. Most antihypertensive medications interfere to some extent with these tests, in particular ACE inhibitors or angiotensin-receptor blockers (ARBs), making interpretation difficult. For this reason, it is preferable that such patients are not commenced on antihypertensive medication until they have been seen by a hypertension specialist. However, if the blood pressure is severely raised and/or the patient is symptomatic, treatment initiation should not be delayed.
Obstructive sleep apnoea (OSA) is another important yet often overlooked secondary cause of hypertension.13 Mechanisms for the development of hypertension in OSA are incompletely understood but one well-described effect is of intermittent hypoxaemia inducing a sustained increase in sympathetic nervous system activity and decreased levels of the vasodilator nitric oxide.14 Despite continuous positive airways pressure (CPAP) being an effective treatment for OSA, meta-analysis has shown minimal effect on ambulatory BP (1–2 mmHg reduction).15 Further long-term studies are needed to elucidate whether long-term therapeutic correction of OSA leads to a reduction in BP and cardiovascular events.
Figure 2. Magnetic resonance angiogram showing bilateral renal artery stenosis (RAS) in a hypertensive patient. Risk factors for RAS include a history of smoking, diabetes, peripheral arterial disease or coronary artery disease. A significant decline in glomerular filtration rate following initiation of ACE inhibitor or angiotensin-receptor blocker should raise suspicions for RAS
Figure 3. Computed tomography (CT) scan showing a left-sided adrenal mass in a patient with hypertension. Histology confirmed benign adenoma (‘Conn’s syndrome’)
There are well-established lifestyle factors that contribute to high blood pressure, the most well known of which include diet (and dietary salt intake in particular), alcohol consumption, obesity and physical activity. Prescribed medicines and other pharmacologically active substances that affect BP are also important.
Numerous studies have shown a positive association between sodium intake and BP, and patients with resistant hypertension (those requiring three or more antihypertensive drugs) tend to consume more salt than the general population, often more than 10g per day.16 A study that looked at the effects of sodium restriction on patients with resistant hypertension showed that a low-sodium diet reduced ambulatory systolic and diastolic BP by approximately 20 and 10mmHg respectively.17
Alcohol consumption has a linear correlation with BP and prevalence of hypertension. Heavy alcohol intake (more than 14 units per week) and binge drinking are associated with raised BP and an increased risk of stroke. Structured intervention to reduce alcohol intake has been shown to lead to significant reductions in BP.18 The link between obesity and hypertension is most likely due to the association with sodium retention, sympathetic nervous system overactivity and activation of the renin-angiotensin-aldosterone system, as well as the clear association with OSA.16
Use of prescribed, over-the-counter, herbal and illicit substances may cause high blood pressure or interfere with the BP-lowering effects of antihypertensive drugs. Enquiry about the use of these substances should be routine. Examples include sympathomimetic recreational drugs such as cocaine and amphetamines, NSAIDs, oestrogen-containing contraceptives, steroids, nasal decongestants such as pseudoephedrine, erythropoietin, ciclosporin, liquorice (which suppresses the metabolism of cortisol), anorexics such as phentermine, and herbal supplements such as ephedra.19 Sodium-containing effervescent, dispersible and soluble drugs have also been associated with significantly increased odds of cardiovascular events compared with standard formulations of the same drugs, most likely due to the increased risk of hypertension shown in the study.20 Medicines with high sodium content such as sodium alginates should be avoided, if possible.
Drug treatment options and their efficacy
Drug treatment of hypertension in the UK should generally follow the BIHS/NICE guidelines.6 Recommendations have changed over time in light of new research, and new NICE guidance is currently in consultation. First-line treatment recommendations are based on age and ethnicity. The main rationale for this, which is not always appreciated, is the baseline renin activity of the patient. Older patients and those of Black African/Caribbean ethnicity tend to have low renin activity – if renin is measured in the blood, it is likely to be low or undetectable. This is why commencing a patient with low renin hypertension on an ACE inhibitor or ARB as a single antihypertensive agent is likely to be ineffective and hence, calcium-channel blockers are recommended as first-line drugs in theses populations. Calcium-channel blockers cause activation of the renin-angiotensin system and a secondary rise in renin is observed, which is why addition of an ACE inhibitor or ARB as a second agent when required, results in a synergistic antihypertensive effect.
The 2018 ESC/ESH guidelines now advocate starting single-pill combination treatment at initiation in the majority of patients (using an ACE inhibitor or ARB plus a calcium-channel blocker or diuretic).5 This represents a significant shift in treatment strategy and has not been advocated in the draft of the updated BIHS/NICE guidelines. Combination tablets are more expensive and although potentially useful in a subset of patients, would have a significant cost implication to the NHS.
The ideal combination for patients requiring three drugs to control their BP is a calcium-channel blocker, an ACE inhibitor or ARB, and a thiazide-like diuretic. ACE inhibitors and ARBs should not be used together due to the increased risk of acute kidney injury. Patients with poorly controlled BP despite being prescribed three antihypertensive drugs should be referred to a specialist for further investigation and management (see Table 2).
In those patients adherent to three antihypertensive drugs but still with uncontrolled BP, what to recommend as a fourth-line drug had been undefined until relatively recently. The PATHWAY-2 trial clearly showed that spironolactone was more effective than bisoprolol and doxazosin as an add-on drug in patients with resistant hypertension, supporting the theory that excessive sodium retention has a primary role in this condition.21 This was the case irrespective of baseline plasma renin, but was far more likely to work in patients with lower renin activity. It should be noted that spironolactone is not actually licensed for hypertension in the UK, so its use as an antihypertensive is off-label but common and accepted practice.
Drugs such as beta-blockers and thiazide diuretics have fallen out of favour as first-line drugs for hypertension, partly due to their effects on glucose tolerance and long-term increased risk of developing diabetes. However, co-morbidities will often influence which drugs are most beneficial for an individual. Beta-blockers would be indicated in patients with ischaemic heart disease and heart failure with reduced ejection fraction, and may be useful in patients with atrial fibrillation. Men who also have bladder outflow obstruction may benefit from alpha-adrenoceptor antagonists. Conversely, thiazide diuretics may best be avoided in patients with recurrent attacks of gout and must be avoided in patients with a history of thiazide-induced hyponatraemia.
Multiple drug intolerance is a common indication for referral to secondary care. For example, peripheral oedema is a frequent reason for discontinuing the calcium-channel blocker amlodipine, which is considered a first-line antihypertensive drug in older patients over 55 years of age and those of Black ethnicity. However, calcium-channel blockers are generally the most effective drugs in this cohort of patients, and, as mentioned above, switching to an ACE inhibitor or ARB in this instance is unlikely to be efficacious. A suggested treatment algorithm for patients intolerant to amlodipine as a first-line drug is shown in Figure 4.
Figure 4. Suggested treatment algorithm for hypertensive patients over 55 years of age or of Black African/Caribbean ethnicity, who are intolerant to first-line treatment with a dihydropyridine calcium-channel blocker (CCB), eg amlodipine (assuming there are no contraindications to individual drugs)
Interventional device-based techniques to lower blood pressure have been extensively researched in recent years, with renal denervation being the most widely studied. Initial enthusiasm for the procedure waned following publication of the landmark SYMPLICITY HTN-3 trial, the first single-blinded, randomised, sham-controlled trial.22 Unfortunately, there was not a statistically significant reduction in BP in the renal denervation group compared with the sham procedure group. This procedure is therefore not routinely carried out on the NHS. Renal denervation may yet find a niche in well-selected patients with the advancement of more sophisticated devices, although further evidence is required.
Needless to say, drugs only work if they are taken. Although effective and well-tolerated once-daily antihypertensive medications are widely available, poor concordance with recommended treatments continues to be one of the main causes of unsatisfactory BP control.23 Estimates vary but the extent to which patients adhere to prescribed medications for hypertension is between 50% and 70%.24
In one longitudinal study using a database of nearly 5000 patients prescribed once-a-day antihypertensive drugs, patients’ dosing histories were electronically compiled using a Medication Event Monitoring System (MEMS).25 By the end of one year, almost half of the patients had stopped taking the antihypertensive medication. There was an initial abrupt drop of 2%, which represents patients who never engage with the dosing regimen. On each day of treatment, about 10% of scheduled doses were omitted, almost 95% of patients missed a single dose, and about 50% of patients took a ‘drug holiday’ of more than 48 hours.
Use of urine testing to measure adherence in specialist hypertension clinics in the UK has become routine in recent years. Studies in this setting using high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) of random urine samples have shown that up to half of patients were totally or partially non-adherent to antihypertensive treatment.26 Healthcare professionals should therefore have a high index of suspicion for non-adherence in patients with poor BP control despite being prescribed multiple antihypertensives. A non-judgemental and non-confrontational approach to the issue is recommended when discussing this with the patient, in order to avoid a breakdown in the patient-clinician relationship.
Strategies to improve adherence should be tailored to the individual because patients have different reasons for non-adherence. Intolerance to medication is a common factor26 and patients with multiple drug intolerance should be referred to a hypertension specialist (see Table 2).
Hypertension is a major modifiable risk factor for cardiovascular disease and death and is one of the most researched areas of medicine, but conflicting opinions remain about optimal blood pressure targets. Treating patients to stricter BP targets may result in fewer cardiovascular events, but will lead to more medication-related adverse events. Guidelines continue to be adapted based on new evidence, so it is important to stay up-to-date.
New research has guided strategies for managing patients with mild hypertension and drug-resistant hypertension more effectively. Urine adherence screening is now routine practice in secondary care and may become so in primary care. Patients younger than 40 years of age should be judiciously screened for underlying causes of hypertension by a specialist.
Declaration of interests
None to declare.
Dr Mark Pucci is a Consultant in Clinical Pharmacology and Therapeutics and General Internal Medicine at The Queen Elizabeth Hospital in Birmingham
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