Diagnosis and treatment
Background: Essential arterial hypertension is one of the main treatable cardiovascular risk factors. In Germany, approximately 13% of women and 18% of men have uncontrolled high blood pressure (≥ 140/90 mmHg).
Methods: This review is based on pertinent publications retrieved by a selective literature search in PubMed.
Results: Arterial hypertension is diagnosed when repeated measurements in a doctor’s office yield values of 140/90 mmHg or higher. The diagnosis should be confirmed by 24-hour ambulatory blood pressure monitoring or by home measurement. Further risk factors and end-organ damage should be considered as well. According to the current European guidelines, the target blood pressure for all patients, including those with diabetes mellitus or renal failure, is <140/90 mmHg. If the treatment is well tolerated, further lowering of blood pressure, with a defined lower limit, is recommended for most patients. The main non-pharmacological measures against high blood pressure are reduction of salt in the diet, avoidance of excessive alcohol consumption, smoking cessation, a balanced diet, physical exercise, and weight loss. The first-line drugs for arterial hypertension include long-acting dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and thiazide-like diuretics. Mineralocorticoid-receptor blockers are effective in patients whose blood pressure cannot be brought into acceptable range with first-line drugs.
Conclusion: In most patients with essential hypertension, the blood pressure can be well controlled and the cardiovascular risk reduced through a combination of lifestyle interventions and first-line antihypertensive drugs.
The World Health Organization estimates that 54% of strokes and 47% of cases of ischemic heart disease are the direct consequence of high blood pressure, which thus takes its place among the main risk factors for cardiovascular morbidity and mortality (1). The declining incidence of stroke in recent decades is accounted for in large measure by the reduction of blood pressure (2). Even though the epidemiological association between high blood pressure and cardiovascular morbidity and mortality is well known, and despite the fact that sufficient evidence exists to justify antihypertensive treatment (3), blood pressure is often not adequately controlled. Either the blood pressure is not measured, or the physician fails to react in the face of elevated blood pressure values (4), or treatment is not provided optimally, or the patient fails to take the necessary medication regularly (5). In patients who suffer from treatment-resistant arterial hypertension, the blood pressure cannot be adequately controlled even if the patient does take the prescribed medication regularly. In patients with essential hypertension, none of the currently available clinical methods can detect a specific cause of the elevated blood pressure. Causes of secondary hypertension such as renal artery stenosis, hyperaldosteronism, or pheochromocytoma, must be considered in the differential diagnosis, particularly in younger patients and those whose blood pressure is hard to control. Secondary types of hypertension call for specific diagnostic and therapeutic approaches (e.g., a pheochromocytoma must be resected) and will not be discussed here. In what follows, we provide an overview of the epidemiology and pathophysiology of essential arterial hypertension and derive recommendations for the treatment of the affected patients.
This article should enable the reader to
- diagnose arterial hypertension and treat this leading cardiovascular risk factor,
- be familiar with the definition of blood pressure target values for treatment, and
- know how to treat patients in conformity with the current guidelines.
A selective search for original articles and reviews was carried out in PubMed with special attention to current guidelines and meta-analyses, which are given here as references. This article is also based on the authors’ scientific and clinical experience.
In the 1990s, the prevalence of arterial hypertension in Germany was still higher than the mean value among other Western countries. German epidemiological data from the years 2008–2011 reveal a decline in the frequency of uncontrolled hypertension from 22% to 13% in women and from 24% to 18% in men (Figure 1) (6). Meanwhile, however, the prevalence among men aged 18 to 29 rose from 4.1% to 8.5%.
Elevated blood pressure must be due to elevated cardiac output, elevated peripheral vascular resistance, or a combination of both. Each of these mechanisms is regulated, in turn, by hemodynamic, neural, humoral, and renal processes, all of which vary in their contribution from one individual to another (Figure 2). As persons grow older, the predominant cause of hypertension tends to be elevated peripheral vascular resistance, often in combination with increased stiffness of the vessels, which manifests itself clinically as isolated systolic hypertension (7). Familial clustering implies a genetic predisposition whose interaction with environmental factors, such as the intake of salt and calories and the degree of physical exercise, ultimately determines how severe the rise of blood pressure will be.
Diagnostic evaluation and screening
In their current, updated joint guidelines on the diagnosis and treatment of arterial hypertension (8), the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) retain the threshold value of ≥ 140/90 mm Hg for the definition of high blood pressure when measured in a doctor’s office. At least three measurements should be made on each of several days, with 1–2 minutes between measurements and with a 3–5 minute pause before blood pressure is measured with the patient sitting. The optimal conditions for blood pressure measurement should be maintained (Box 1). Measurements from the arm in patients with an arm circumference of 22–32 cm are made with a standard cuff (12–13 cm wide, 35 cm long); for larger upper arms, cuffs that are 15–18 cm wide are available. When the blood pressure is first measured, it should be measured on both sides. If the difference in the values obtained on the two sides is >20 mmHg systolic or >10 mmHg diastolic, the following potential causes must be ruled out, and, if the blood pressure is lower on the left side, the possibility of an aortic isthmus stenosis should be considered:
- Aortic arch syndrome due to atherosclerosis, or, rarely, vasculitis;
- Unilateral subclavian artery stenosis;
- Aortic dissection.
Further measurements are subsequently always made on the arm with the higher values. Orthostatic hypotension is defined as a fall in blood pressure by more than 20 mmHg systolic and/or more than 10 mmHg diastolic after the patient has been standing for three minutes (9). If orthostatic hypotension is suspected, particularly in an elderly or diabetic patient, two further measurements should be made 1 and 3 minutes later, with the patient still standing.
The diagnosis should be confirmed by a 24-hour ambulatory measurement or by automated home blood pressure measurements. The values obtained by these methods are usually lower than those obtained in the doctor’s office. This fact is taken into account by the lower recommended cutoff values (8). A 24-hour ambulatory measurement is also particularly helpful for ascertaining the presence of white-coat hypertension or of masked hypertension.
A patient with white-coat hypertension regularly has an elevated blood pressure in the doctor’s office, but normal values when measured at home. The prevalence of this phenomenon in the general population is approximately 13% (10). The long-term risk of cardiovascular events may be slightly higher in persons with white-coat hypertension than in persons without it (11).
In contrast, masked hypertension is the situation in which the measured blood pressure values are normal in the doctor’s office, but elevated at home. It is more common in young people, males, smokers, overweight or diabetic persons, and those suffering from anxiety or stress (12). The incidence of cardiovascular events in persons with masked hypertension is similar to that of persons with persistently elevated blood pressure (13).
10–15% of persons with hypertension have secondary hypertension due to a potentially treatable cause. If the history and basic diagnostic assessment suggest this possibility (Box 2), a targeted supplementary evaluation should be performed (Table 1). The patient should be asked about his or her intake of substances that elevate blood pressure, including licorice, amphetamines, cocaine, oral contraceptive drugs, mineralo- and glucocorticoids, nonsteroidal anti-inflammatory drugs, erythropoietin, and cyclosporine. Anticancer drugs, particularly angiogenesis inhibitors and tyrosine kinase inhibitors, can also elevate blood pressure.
High blood pressure is usually accompanied by other cardiovascular risk factors that further potentiate the risk. It follows that an evaluation of the patient’s overall risk should always be the first objective (Box 3).
According to the current recommendation, the higher the patient’s overall cardiovascular risk, the more strictly the blood pressure should be controlled and the earlier drug treatment should be initiated (Figure 4) (8). Moreover, before any treatment is given, the potential causes of secondary hypertension should be excluded (Table 1). The possibility of pseudoresistance to treatment due to white-coat hypertension or suboptimal drug compliance should be borne in mind. Compliance can be checked by blood pressure measurement after supervised drug intake, or else by measurement of the active substance(s) in the patient’s serum or urine. These factors are too often left out of consideration, even by specialists (14). In one study, out of 731 patients carrying the diagnosis of treatment-resistant hypertension, 26.5% actually had either pseudoresistant essential hypertension or a secondary type of hypertension. In 47% of cases, blood pressure became normal after a suitable change in the drug regimen (14).
Target values for blood pressure
According to the update of the European ESH/ESC guidelines (2018), all patients, including those with renal failure or diabetes, should have their blood pressure reduced to less than 140/90 mmHg (as measured in the doctor’s office) at the beginning of their treatment (8). Most patients will tolerate this well; for those who do, a further reduction of blood pressure is recommended. A target blood pressure range is defined, including a lower limit (8). For patients aged 18–65, a target systolic blood pressure below 130 mmHg, but no less than 120 mmHg is suggested. The same holds for diabetic patients, whereas the recommendation for patients with renal failure is a somewhat higher target systolic blood pressure range (below 140 mmHg, but no less than 130 mmHg). For patients over age 65, the recommended target systolic blood pressure range is also below 140 mmHg, but no less than 130 mmHg. The target diastolic blood pressure range for all patients, regardless of age, is below 80 mmHg, but no less than 70 mmHg. In elderly patients in particular, attention must be paid to side effects, and the blood pressure target may have to be reset. The available scientific evidence on the treatment of high blood pressure in the elderly is limited, because the elderly are often excluded from clinical trials (15).
The German High Blood Pressure League recommends the reduction of blood pressure to less than 135/85 mmHg only in patients who have a high cardiovascular risk (16), stating that the advantage of low systolic blood pressure has not yet been demonstrated for hypertensive patients who suffer from diabetes mellitus, have already sustained a stroke, or are physically handicapped or dependent on nursing care.
The U.S. American cardiological societies, in the most recent update of their guidelines, classify blood pressure values in the range of 130–139/85–89 mmHg as grade I hypertension, but state that this should initially be treated without drugs in most cases (Figure 3) (17, 18). In the updated European guidelines, this is designated as the upper range of normal blood pressure, and it is recommended that drug treatment be considered for patients with blood pressure in this range only if their cardiovascular risk is very high (Figure 4) (8). More liberal cutoff values for high blood pressure are set by the United Kingdom’s National Institute for Health and Care Excellence (NICE) (19), which defines hypertension as an initial measurement ≥ 140/90 mm Hg with subsequent measurements ≥ 135/85 mm Hg (Figure 3).
The association of blood pressure with the occurrence of cardiovascular events in patients at high risk can be depicted by a J-shaped curve: over-aggressive blood pressure reduction (to <120 mmHg systolic or <70 mmHg diastolic) only causes more side effects without any further reduction of cardiovascular events (20). On the other hand, the findings of the Systolic Pressure Intervention Trial (SPRINT) contributed to a downward trend in blood pressure cutoff values in the U.S. American and European guidelines. In this trial, 9361 patients over age 50 with a high cardiovascular risk, but without diabetes mellitus, were randomized to systolic blood pressure reduction to either <120 mmHg or <140 mm Hg (21). Over a mean follow-up time of 3.26 years, the patients with the lower blood pressure target had a lower incidence of a combined cardiovascular endpoint (hazard ratio [HR]: 0.75, 95% confidence interval: [0.64; 0.89]) and a lower risk of death from a cardiovascular cause (HR: 0.57 [0.38; 0.85]. The patients with the lower blood pressure target achieved a mean systolic blood pressure of 121 mmHg over a three-year period by taking a mean of 2.8 antihypertensive drugs, while those with the lower target achieved a mean systolic blood pressure of 134 mmHg by taking a mean of 1.8 antihypertensive drugs. The automated blood-pressure measurements in this trial were carried out after a five-minute rest period and without medical supervision, resulting in values that were a mean of 12.7/12.0 mmHg lower than those obtained in a conventional doctor’s office setting (22). It follows that these findings are not directly applicable to routine outpatient care.
A somewhat different picture arose from a Cochrane Review concerning the question whether a reduction of blood pressure by 9.5/4.9 mmHg (down to ≤ 135/85 mmHg from starting values of 140–160/90–100 mmHg) might lower morbidity and mortality in patients already suffering from cardiovascular disease (23). Data derived from 9795 subjects, including data from SPRINT, were evaluated; no difference was seen either in overall mortality (relative risk [RR] 1.05 [0.90; 1.22]) or in cardiovascular mortality (RR 0.96 [0.77; 1.21]). Lower blood pressure did, however, lead to a 1.6% absolute risk reduction for fatal and non-fatal cardiovascular events. A further meta-analysis concerned the effects of reducing blood pressure from 150–160/95–105 mmHg to <140/90 mmHg in elderly patients with a mean age of 75 years (24). A total of 8221 patients from three different trials were included in this meta-analysis, with SPRINT patients excluded for methodological reasons. There was no statistically significant effect on overall mortality, stroke, or serious cardiovascular events. Overall, it was concluded that there is an individual, relatively narrow blood pressure corridor that can be recommended for each patient on the basis of his or her age, comorbidities, and ability to tolerate the treatment. It remains to be seen whether this concept can be practically applied in routine clinical situations.
The two pillars of antihypertensive treatment are non-pharmacological treatment and drug treatment (Figure 4). Lifestyle changes are always to be considered first as a means of lowering blood pressure (8), and it makes sense to maintain these changes even after the later initiation of drug treatment. The most important measures are a low-salt diet, adequate potassium intake, avoidance of excessive alcohol consumption, smoking cessation, a healthy, balanced diet, physical exercise, and weight loss.
In a meta-analysis, the reduction of salt intake from 201 mmol/day (a fairly typical value for the German population) to 66 mmol/day lowered blood pressure by a mean of 5.5/2.9 mmHg in white hypertensive patients (25). The effect is variable, however: not every patient benefits from a low-salt diet. Some antihypertensive drugs, particularly inhibitors of the renin-angiotensin-aldosterone system, tend to be more effective if the patient is on a low-salt diet (26). According to the ESH/ESC guidelines, daily salt intake should not exceed 5 g (8). Potassium intake can be increased by increased consumption of vegetables and fruit.
In randomized controlled trials, regular endurance training lowered blood pressure by a mean of 11/5 mmHg (27, 28). The strongest effect was found in patients who exercised during 40- to 60-minute periods at least three times per week. A meta-analysis revealed that regular dynamic strength training can also positively affect blood pressure (29, 30).
Overweight and obese persons are at higher risk for arterial hypertension, need more antihypertensive medication, and are more commonly resistant to treatment than patients with normal weight (31, 32). It is currently recommended that all persons should have a body-mass index between 20 and 25 kg/m2, with a waist circumference less than 94 cm in men and 80 cm in women (14). The value of weight-reducing drugs for obese hypertensive patients is unclear (33, 34). The massive weight reduction brought about by bariatric surgery is associated with an initial marked improvement in blood pressure (35). Over the long term, however, this effect seems to diminish, and persistent weight reduction by at least 10 kg is needed to lower systolic blood pressure by 6 mmHg [−10.66; −1.38 mmHg] (36).
Drug treatment can be initiated with a single drug or a combined preparation (13, 37). The ESC and ESH, in their updated joint guideline, recommend that most patients should take two antihypertensive drugs at the start of pharmacotherapy, preferably combined in a single tablet (8). The recommended first line of treatment consists of preparations that are constituted from the following four drug classes: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor subtype 1 (AT1) blockers (sartans), long-acting calcium channel blockers of the dihydropyridine type, and thiazide-like diuretics (Table 2). Even though beta-adrenoreceptor blockers are inferior to these substance classes with respect to cardiovascular protection (38), they are considered a suitable component of first-line treatment in some countries. Beta-blockers are used in patients who suffer from angina pectoris, have sustained a myocardial infarction in the past, or have heart failure, or else for the control of heart rate (8). On the one hand, the choice of antihypertensive drug is based on individual efficacy and tolerability, for which there are still no good predictors; on the other hand, certain antihypertensive drugs improve outcomes in patients with certain underlying diseases and should, therefore, be used preferentially in these patients (Figure 5). Preparations with a long half-life that can be given once per day are preferable for reasons of compliance. In view of the circadian rhythms of circulatory regulation, it may be better for patients to take long-acting antihypertensive drugs in the evening (39), but it remains unclear whether this has any positive effect on cardiovascular events.
ACE inhibitors and AT1 receptor antagonists have been extensively studied in large-scale clinical trials (40). They improve the survival of patients with heart failure and have a beneficial effect on diabetic nephropathy, and should therefore be given preferentially to patients with these conditions (Figure 5). They may also lower the risk of developing type 2 diabetes mellitus (e1). Rising creatinine values and a corresponding drop in the estimated glomerular filtration rate (eGFR) by as much as 30% after the initiation of treatment with an ACE inhibitor or an AT1 receptor antagonist are not infrequently seen, particularly in patients with diabetic nephropathy, and should not necessarily prompt the physician to discontinue these drugs. This phenomenon is due to the desired reduction of the blood pressure faced by the renal glomeruli, resulting in a functional reduction of the eGFR. AT1 receptor antagonists carry a much lower risk of inducing cough and angioedema, but their side-effect profile is similar to that of ACE inhibitors in other respects (e2).
Calcium channel blockers of the dihydropyridine type are effective antihypertensive drugs and can, in principle, be combined with any other type of first-line antihypertensive drug. Peripheral edema due to peripheral vasodilatation is a common side effect and sometimes leads to discontinuation of the drug (18). In a Cochrane analysis, the incidence of peripheral edema was 38% lower when the calcium channel blocker was given in combination with an ACE inhibitor or an AT1 receptor antagonist, probably because of the relaxation of post-capillary resistance vessels brought about by the second drug (e3). calcium channel blockers can cause or worsen constipation, particularly in elderly and immobile patients. They can also cause clinically significant drug interactions by inhibiting the enzyme cytochrome P450 3A4.
Thiazide-like diuretics have been a mainstay of antihypertensive treatment for decades (e4). Hydrochlorothiazide is the one most commonly prescribed around the world, even though it seems to be less effective than indapamide or chlorthalidone (e5). Electrolyte disturbances are a common side effect, especially in elderly patients (e6); the main types are hyponatremia and hypokalemia. 4.1% of elderly hypertensive patients treated with chlorthalidone had a serum sodium concentration below 130 mmol/L (e7). The risk of hypokalemia is lower when a thiazide diuretic is given in combination with an ACE inhibitor, an AT1 receptor antagonist, or a potassium-sparing diuretic.
Beta-blockers are inferior to other first-line antihypertensive drugs for the reduction of blood pressure (13, e8). They can cause weight gain (e9). Non-vasodilating beta-blockers have a deleterious effect on glucose metabolism (e10). Beta-blockers may worsen bronchoconstriction in patients with asthma. Nor should they be combined with verapamil or diltiazem, two drugs that can slow the sinus rhythm or prolong atrioventricular conduction. Beta-blockers do improve the prognosis of patients who have sustained an acute myocardial infarction and/or suffer from chronic congestive heart failure, and they are, therefore, indicated for patients with these conditions, independently of their antihypertensive effect (8).
ACE inhibitors and AT1 receptor antagonists are contraindicated during pregnancy. Pregnant women may take older antihypertensive drugs such as dihydralazine and alpha-methyldopa; they may also take beta-blockers, such as metoprolol, and extended-release nifedipine. Dihydralazine and nifedipine, however, should not be given during the first trimester (e11).
Even when all of these measures are taken, some 10% of hypertensive patients treated in routine clinical practice do not achieve adequate blood pressure control (e12, e13). The definition of treatment-resistant hypertension is blood pressure that persistently remains over 140/90 mmHg despite treatment with three antihypertensive drugs in optimal doses, one of which is a diuretic. The definition also requires the exclusion of potential causes of secondary hypertension. Treatment-resistant hypertension often turns out to be treatable once the matter of patient compliance and the potential for further improvement of the drug regimen have been properly addressed; in our experience, the true prevalence of treatment-resistant hypertension is closer to 4–5%. In these patients, the therapeutic spectrum must be widened in order to counteract the still unaltered, high cardiovascular risk.
The treatment should be directed against two main pathophysiological mechanisms: overactivity of the sympathetic nervous system and volume excess due to excessive sodium retention, renal failure, or an excessively high aldosterone level. Hypervolemia can be countered with high-dose diuretics or with supplementary treatment with a mineralocorticoid-receptor antagonist. This was confirmed in the Pathway 2 trial (e14): 285 hypertensive patients whose mean blood pressure, measured in the doctor’s office, was 157/90 mmHg under standard treatment with an ACE inhibitor or AT1 blocker, a calcium antagonist, and a diuretic at the highest tolerated doses were given either spironolactone (25–50 mg), doxazosine (4–8 mg), bisoprolol (5–10 mg), or placebo for a period of 12 weeks in a double-blind crossover trial. If tolerated, the dose was doubled at 6 weeks. Absolute reduction of blood pressure was most pronounced with spironolactone (values of −12.8 mm Hg, −8.7 mm Hg, −8.3 mm Hg, and –4.1 mmHg, respectively). Blood pressure became normal under this treatment in 58% of patients. The frequency of serious side effects and the treatment discontinuation rate did not differ among treatment groups. Elevated activity of the sympathetic nervous system (e15) also provides the rationale for some of the interventional techniques that have been developed for this group of patients.
The treatment of arterial hypertension with a combination of lifestyle interventions and drugs can markedly lower cardiovascular risk. In most patients, blood pressure can be lowered effectively with first-line antihypertensive drugs, but monotherapy often does not suffice. With regard to blood pressure target values, many questions remain open. We expect that the newly altered target values will give rise to a lively discussion of their advantages and potential risks in the very near future.
Conflict of interest statement
Prof. Jordan has served as a paid scientific consultant for Bayer, Eternygen, Johnson & Johnson, Novartis, Novo-Nordisk, and Theravance. He is a co-founder of Eternygen GmbH.
Prof. Reuter has received lecture fees from, and has served as a paid consultant for, Bayer, Cordis, CVRx, Medtronic, and Servier.
Prof. Kurschat states that he shas no conflict of interest.
Manuscript submitted on 28 November 2017, revised version accepted on 17 July 2018.
Translated from the original German by Ethan Taub, M.D.
Prof. Dr. med. Jens Jordan
Institut für Luft- und Raumfahrtmedizin
Deutsches Zentrum für Luft- und Raumfahrt (DLR)
Linder Höhe,D-51147 Cologne, Germany
For eReferences please refer to:
Department II of Internal Medicine, Divisions of Nephrology, Rheumatology, Diabetes and General Internal Medicine, University Hospital of Cologne, Germany: Prof. Dr. med. Christine Kurschat
Department of Internal Medicine and Cardiology, Evangelisches Klinikum Köln Weyertal, Cologne: Prof. Dr. med. Hannes Reuter
Department III of Internal Medicine, Cardiac Center, University Hospital of Cologne, Germany: Prof. Dr. med. Hannes Reuter
University Hypertension Center, University of Cologne, Germany: Prof. Dr. med. Jens Jordan,
Prof. Dr. med.
Christine Kurschat, Prof. Dr. med. Hannes Reuter
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