2013 ESH/ESC Guidelines for the management of arterial hypertension

Figures & data

Table I. Classes of recommendations.

Classes of recommendations	Definition	Suggested wording to use
Class I	Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective.	Is recommended/is indicated
Class II	Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure.
Class IIa	Weight of evidence/opinion is in favour of usefulness/efficacy.	Should be considered
Class IIb	Usefulness/efficacy is less well established by evidence/opinion.	May be considered
Class III	Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful.	Is not recommended

Table II. Levels of Evidence.

Level of evidence A	Data derived from multiple randomized clinical trials or meta-analyses.
Level of evidence B	Data derived from a single randomized clinical trial or large non-randomized studies.
Level of evidence C	Consensus of opinion of the experts and/or small studies, retrospective studies, registries.

Table III. Definitions and classification of office blood pressure levels (mmHg).^a

Category	Systolic		Diastolic
Optimal	< 120	and	< 80
Normal	120–129	and/or	80–84
High normal	130–139	and/or	85–89
Grade 1 hypertension	140–159	and/or	90–99
Grade 2 hypertension	160–179	and/or	100–109
Grade 3 hypertension	≤ 180	and/or	≤ 110
Isolated systolic hypertension	≤ 140	and	< 90

^aThe blood pressure (BP) category is defined by the highest level of BP, whether systolic or diastolic. Isolated systolic hypertension should be graded 1, 2, or 3 according to systolic BP values in the ranges indicated.

Figure 1. Stratification of total CV risk in categories of low, moderate, high and very high risk according to SBP and DBP and prevalence of RFs, asymptomatic OD, diabetes, CKD stage or symptomatic CVD. Subjects with a high normal office but a raised out-of-office BP (masked hypertension) have a CV risk in the hypertension range. Subjects with a high office BP but normal out-of-office BP (whitecoat hypertension), particularly if there is no diabetes, OD, CVD or CKD, have lower risk than sustained hypertension for the same office BP.

Table IV. Factors—other than office BP—influencing prognosis; used for stratification of total CV risk in Figure 1.

Risk factors

Male sex

Age (men ≤ 55 years; women ≤ 65 years)

Smoking

Dyslipidaemia

Total cholesterol > 4.9 mmol/L (190 mg/dL), and/or

Low-density lipoprotein cholesterol > 3.0 mmol/L (115 mg/dL), and/or

High-density lipoprotein cholesterol: men < 1 mmol/L (40 mg/dL), women < l.2 mmol/L (46 mg/dL), and/or

Triglycerides > l.7 mmol/L (150 mg/dL)

Fasting plasma glucose 5.6–6.9 mmol/L (102–125 mg/dL)

Abnormal glucose tolerance test

Obesity [BMI ≤ 30 kg/m^2 (height^2)]

Abdominal obesity (waist circumference: men ≤ 102 cm; women ≤ 88 cm) (in Caucasians)

Family history of premature CVD (men aged < 55 years; women aged < 65 years)

Asymptomatic organ damage

Pulse pressure (in the elderly) ≤ 60 mmHg

Electrocardiographic LVH (Sokolow–Lyon index > 3.5 mV; RaVL > 1.1 mV; Cornell voltage duration product > 244 mV*ms), or

Echocardiographic LVH [LVM index: men > 115 g/m^2; women > 95 g/m^2 (BSA)]^a

Carotid wall thickening (IMT > 0.9 mm) or plaque

Carotid–femoral PWV > 10 m/s

Ankle-brachial index < 0.9

CKD with eGFR 30–60 mL/min/l.73 m^2 (BSA)

Microalbuminuria (30–300 mg/24 h), or albumin–creatinine ratio (30–300 mg/g; 3.4–34 mg/mmol) (preferentially on morning spot urine)

Diabetes mellitus

Fasting plasma glucose ≤ 7.0 mmol/L (126 mg/dL) on two repeated measurements, and/or

HbA1c > 7% (53 mmol/mol), and/or

Post-load plasma glucose > 11.0 mmol/L (198 mg/dL)

Established CV or renal disease

Cerebrovascular disease: ischaemic stroke; cerebral haemorrhage; transient ischaemic attack

CHD: myocardial infarction; angina; myocardial revascularization with PCI or CABG

Heart failure, including heart failure with preserved EF

Symptomatic lower extremities peripheral artery disease

CKD with eGFR < 30 mL/min/1.73 m^2 (BSA); proteinuria (> 300 mg/24 h).

Advanced retinopathy: haemorrhages or exudates, papilloedema

BMI: body mass index; BP: blood pressure; BSA: body surface area; CABG: coronary artery bypass graft; CHD: coronary heart disease; CKD: chronic kidney disease; CV: cardio–vascular; CVD: cardiovascular disease; EF: ejection fraction; eGFR: estimated glomerular filtration rate; HbA: glycated haemoglobin; IMT: intima-media thickness; LVH: left ventricular hypertrophy; LVM: left ventricular mass; PCI: percutaneous coronary intervention; PWV: pulse wave velocity.

^aRisk maximal for concentric LVH: increased LVM index with a wall thickness/radius ratio of > 0.42.

Total cardiovascular risk assessment.

Recommendations	Class^a	Level^b	Ref.^c
In asymptomatic subjects with hypertension but free of CVD, CKD, and diabetes, total CV risk stratification using the SCORE model is recommended as a minimal requirement.	I	B	43
As there is evidence that OD predicts CV death independently of SCORE, a search for OD should be considered, particularly in individuals at moderate risk.	IIa	B	51, 53
It is recommended that decisions on treatment strategies depend on the initial level of total CV risk.	I	B	41, 42, 50

CKD: chronic kidney disease; CV: cardiovascular; CVD: cardiovascular disease; OD: organ damage; SCORE: Systematic COronary Risk Evaluation.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Table V. Office blood pressure measurement.

When measuring BP in the office, care should be taken:

• To allow the patients to sit for 3–5 minutes before beginning BP measurements. • To take at least two BP measurements, in the sitting position, spaced 1–2 min apart, and additional measurements if the first two are quite different. Consider the average BP if deemed appropriate. • To take repeated measurements of BP to improve accuracy in patients with arrhythmias, such as atrial fibrillation. • To use a standard bladder (12–13 cm wide and 35 cm long), but have a larger and a smaller bladder available for large (arm circumference > 32 cm) and thin arms, respectively. • To have the cuff at the heart level, whatever the position of the patient. • When adopting the auscultatory method, use phase I and V (disappearance) Korotkoff sounds to identify systolic and diastolic BP, respectively. • To measure BP in both arms at first visit to detect possible differences. In this instance, take the arm with the higher value as the reference. • To measure at the first visit, BP 1 and 3 min after assumption of the standing position in elderly subjects, diabetic patients, and in other conditions in which orthostatic hypotension may be frequent or suspected. • To measure, in case of conventional BP measurement, heart rate by pulse palpation (at least 30 s) after the second measurement in the sitting position.

BP: blood pressure.

Table VI. Definitions of hypertension by office and out-of-office blood pressure levels.

Category	Systolic BP (mmHg)		Diastolic BP (mmHg)
Office BP	≤ 140	and/or	≤ 90
Ambulatory BP
Daytime (or awake)	≤ 135	and/or	≤ 85
Nighttime (or asleep)	≤ 120	and/or	≤ 70
24-h	≤ 130	and/or	≤ 80
Home BP	≤ 135	and/or	≤ 85

BP: blood pressure.

Table VII. Clinical indications for out-of-office blood pressure measurement for diagnostic purposes.

Clinical indications for HBPM or ABPM

• Suspicion of white-coat hypertension

– Grade 1 hypertension in the office

– High office BP in individuals without asymptomatic organ damage and at low total CV risk

• Suspicion of masked hypertension

– High normal BP in the office

– Normal office BP in individuals with asymptomatic organ damage or at high total CV risk

• Identification of white-coat effect in hypertensive patients

* Considerable variability of office BP over the same or different visits

• Autonomic, postural, post-prandial, siesta- and drug-induced hypotension

* Elevated office BP or suspected pre-eclampsia in pregnant women

* Identification of true and false resistant hypertension

Specific indications for ABPM

• Marked discordance between office BP and home BP

• Assessment of dipping status

• Suspicion of nocturnal hypertension or absence of dipping, such as in patients with sleep apnoea, CKD, or diabetes

•Assessment of BP variability

ABPM: ambulatory blood pressure monitoring; BP: blood pressure; CKD: chronic kidney disease; CV: cardiovascular; HBPM: home blood pressure monitoring.

Table VIII. Personal and family medical history.

1. Duration and previous level of high BP, including measurements at home

2. Secondary hypertension

a) Family history of CKD (polycystic kidney)

b) History of renal disease, urinary tract infection, haematuria, analgesic abuse (parenchymal renal disease)

c) Drug/substance intake, e.g. oral contraceptives, liquorice, carbenoxolone, vasoconstrictive nasal drops, cocaine, amphetamines, gluco- and mineralocorticosteroids, non-steroidal anti-inflammatory drugs, erythropoietin, cyclosporine

d) Repetitive episodes of sweating, headache, anxiety, palpitations (pheochromocytoma)

e) Episodes of muscle weakness and tetany (hyperaldosteronism)

f) Symptoms suggestive of thyroid disease

3. Risk factors

a) Family and personal history of hypertension and CVD

b) Family and personal history of dyslipidaemia

c) Family and personal history of diabetes mellitus (medications, blood-glucose levels, polyuria)

d) Smoking habits

e) Dietary habits

f) Recent weight changes; obesity

g) Amount of physical exercise

h) Snoring; sleep apnoea (information also from partner)

i) Low birth-weight

4. History and symptoms of organ damage and cardiovascular disease

a) Brain and eyes: headache, vertigo, impaired vision, TIA, sensory or motor deficit, stroke, carotid revascularization

b) Heart: chest pain, shortness of breath, swollen ankles, myocardial infarction, revascularization, syncope, history of palpitations, arrhythmias, especially atrial fibrillation

c) Kidney: thirst, polyuria, nocturia, haematuria

d) Peripheral arteries: cold extremities, intermittent claudication, pain-free walking distance, peripheral revascularization

e) History of snoring/chronic lung disease/sleep apnoea

f) Cognitive dysfunction

5. Hypertension management

a) Current antihypertensive medication

b) Past antihypertensive medication

c) Evidence of adherence or lack of adherence to therapy

d) Efficacy and adverse effects of drugs

BP: blood pressure; CKD: chronic kidney disease; CVD: cardiovascular disease; TIA: transient ischaemic attack.

Table IX. Physical examination for secondary hypertension, organ damage and obesity.

Signs suggesting secondary hypertension

• Features of Cushing syndrome.

• Skin stigmata of neurof bromatosis (pheochromocytoma).

• Palpation of enlarged kidneys (polycystic kidney).

• Auscultation of abdominal murmurs (renovascular hypertension).

• Auscultation of precordial or chest murmurs (aortic coarctation; aortic disease; upper extremity artery disease).

• Diminished and delayed femoral pulses and reduced femoral blood pressure compared to simultaneous arm BP (aortic coarctation; aortic disease; lower extremity artery disease).

• Left-right arm BP difference (aortic coarctation; subclavian artery stenosis).

Signs of organ damage

• Brain: motor or sensory defects.

• Retina: fundoscopic abnormalities.

• Heart: heart rate, 3^rd or 4^th heart sound, heart murmurs, arrhythmias, location of apical impulse, pulmonary rales, peripheral oedema.

• Peripheral arteries: absence, reduction, or asymmetry of pulses, cold extremities, ischaemic skin lesions.

• Carotid arteries: systolic murmurs.

Evidence of obesity

• Weight and height.

• Calculate BMI: body weight/height^2 (kg/m^2).

• Waist circumference measured in the standing position, at a level midway between the lower border of the costal margin (the lowest rib) and uppermost border of the iliac crest.

BP: blood pressure; BMI: body mass index.

Blood pressure measurement, history, and physical examination.

Recommendations	Class^a	Level^b	Ref.^C
It is recommended to obtain a comprehensive medical history and physical examination in all patients with hypertension to verify the diagnosis, detect causes of secondary hypertension, record CV risk factors, and to identify OD and other CVDs.	I	C	–
Obtaining a family history is recommended to investigate familial predisposition to hypertension and CVDs.	I	B	143, 144
Office BP is recommended for screening and diagnosis of hypertension.	I	B	3
It is recommended that the diagnosis of hypertension be based on at least two BP measurements per visit and on at least two visits.	I	C	–
It is recommended that all hypertensive patients undergo palpation of the pulse at rest to determine heart rate and to search for arrhythmias, especially atrial fibrillation.	I	B	62, 63
Out-of-office BP should be considered to confirm the diagnosis of hypertension, identify the type of hypertension, detect hypotensive episodes, and maximize prediction of CV risk.	IIa	B	89, 90, 103, 105, 109, 113, 117
For out-of-office BP measurements, ABPM or HBPM may be considered depending on indicaton, availability, ease, cost of use and, if appropriate, patient preference.	IIb	C	–

ABPM: ambulatory blood pressure monitoring; BP: blood pressure; CV: cardiovascular; CVD: cardiovascular disease; HBPM: home blood pressure monitoring; OD: organ damage.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Table X. Laboratory investigations.

Routine tests

• Haemoglobin and/or haematocrit.

• Fasting plasma glucose.

• Serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol.

• Fasting serum triglycerides.

• Serum potassium and sodium.

• Serum uric acid.

• Serum creatinine (with estimation of GFR).

• Urine analysis: microscopic examination; urinary protein by dipstick test; test for microalbuminuria.

• 12-lead ECG.

Additional tests, based on history, physical examination, and findings from routine laboratory tests

• Haemoglobin A1c (if fasting plasma glucose is > 5.6 mmol/L (102 mg/dL) or previous diagnosis of diabetes).

• Quantitative proteinuria (if dipstick test is positive); urinary potassium and sodium concentration and their ratio.

• Home and 24-h ambulatory BP monitoring.

• Echocardiogram.

• Holter monitoring in case of arrhythmias.

• Exercise testing.

• Carotid ultrasound.

• Peripheral artery/abdominal ultrasound.

• Pulse wave velocity.

• Ankle-brachial index.

• Fundoscopy.

Extended evaluation (mostly domain of the specialist)

• Further search for cerebral, cardiac, renal, and vascular damage, mandatory in resistant and complicated hypertension.

• Search for secondary hypertension when suggested by history, physical examination, or routine and additional tests.

BP: blood pressure; ECG: electrocardiogram; GFR: glomerular filtration rate.

Table XI. Cut-off values for parameters used in the assessment of LV remodelling and diastolic function in patients with hypertension. Based on Lang et al.¹⁵⁸ and Nagueh et al.^168.

Parameter	Abnormal if
LV mass index (g/m^2)	> 95 (women) > 115 (men)
Relative wall thickness (RWT)	> 0.42
Diastolic function: Septal e’ velocity (cm/sec) Lateral e’ velocity (cm/sec) LA volume index (mL/m^2)	< 8 < I0  ≤ 34
LV Filling pressures : E/e’ (averaged) ratio	≤ I3

LA: left atrium; LV: left ventricle; RWT: relative wall thickness.

Table XII. Predictive value, availability, reproducibility and cost–effectiveness of some markers of organ damage.

Marker	Cardiovascular predictive value	Availability	Reproducibility	Cost-effectiveness
Electrocardiography	+++	++++	++++	++++
Echocardiography, plus Doppler	++++	+++	+++	+++
Estimated glomerular filtration rate	+++	++++	++++	++++
Microalbuminuria	+++	++++	++	++++
Carotid intima-media thickness and plaque	+++	+++	+++	+++
Arterial stiffness (pulse wave velocity)	+++	++	+++	+++
Ankle-brachial index	+++	+++	+++	+++
Fundoscopy	+++	++++	++	+++
Additional measurements
Coronary calcium score	++	+	+++	+
Endothelial dysfunction	++	+	+	+
Cerebral lacunae/white matter lesions	++	+	+++	+
Cardiac magnetic resonance	++	+	+++	++

Scores are from + to ++ + +.

Search for asymptomatic organ damage, cardiovascular disease, and chronic kidney disease.

Recommendations	Class^a	Level^b	Ref.^c
Heart
An ECG is recommended in all hypertensive patients to detect LVH, left atrial dilatation, arrhythmias, or concomitant heart disease.	I	B	149, 150, 151, 154
In all patients with a history or physical examination suggestive of major arrhythmias, long-term ECG monitoring, and, in case of suspected exercise-induced arrhythmias, a stress ECG test should be considered.	IIa	C	–
An echocardiogram should be considered to refine CV risk, and confirm ECG diagnosis of LVH, left atrial dilatation or suspected concomitant heart disease, when these are suspected.	IIa	B	156, 158, 160, 163, 164
Whenever history suggests myocardial ischaemia, a stress ECG test is recommended, and, if positive or ambiguous, an imaging stress test (stress echocardiography, stress cardiac magnetic resonance or nuclear scintigraphy) is recommended.	I	C	–
Arteries
Ultrasound scanning of carotid arteries should be considered to detect vascular hypertrophy or asymptomatic atherosclerosis, particularly in the elderly.	IIa	B	51, 183–185, 188
Carotid-femoral PWV should be considered to detect large artery stiffening.	IIa	B	51, 138, 192–195
Ankle-brachial index should be considered to detect PAD.	IIa	B	198, 199
Kidney
Measurement of serum creatinine and estimation of GFR is recommended in all hypertensive patients.^d	I	B	228, 231, 233
Assessment of urinary protein is recommended in all hypertensive patients by dipstick.	I	B	203, 210
Assessment of microalbuminuria is recommended in spot urine and related to urinary creatinine excretion.	I	B	222, 223, 225, 228
Fundoscopy
Examination of the retina should be considered in difficult to control or resistant hypertensive patients to detect haemorrhages, exudates, and papilloedema, which are associated with increased CV risk.	IIa	C	–
Examination of the retina is not recommended in mild-to-moderate hypertensive patients without diabetes, except in young patients.	III	C	–
Brain
In hypertensive patients with cognitive decline, brain magnetic resonance imaging or computed tomography may be considered for detecting silent brain infarctions, lacunar infarctions, microbleeds, and white matter lesions.	IIb	C	–

CV: cardiovascular; ECG: electrocardiogram; GFR: glomerural filtration rate; LVH: left ventricular hypertrophy; MRI: magnetic resonance imaging; PAD: peripheral artery disease; PWV: pulse wave velocity.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

^dThe MDRD formula is currently recommended but new methods such as the CKD-EPI method aim to improve the accuracy of the measurement.

Table XIII. Clinical indications and diagnostics of secondary hypertension.

	Clinical indications			Diagnostics
	Clinical history	Physical examination	Laboratory investigations	First-line test(s)	Additional/ confirmatory test(s)
Common causes
Renal parenchymal disease	History of urinary tract infection or obstruction, haematuria, analgesic abuse; family history of polycystic kidney disease.	Abdominal masses (in case of polycystic kidney disease).	Presence of protein, erythrocytes, or leucocytes in the urine, decreased GFR.	Renal ultrasound	Detailed work-up for kidney disease.
Renal artery stenosis	Fibromuscular dysplasia: early onset hypertension (especially in women). Atherosclerotic stenosis: hypertension of abrupt onset, worsening or increasingly difficult to treat; flash pulmonary oedema.	Abdominal bruit	Difference of > 1.5 cm in length between the two kidneys (renal ultrasound), rapid deterioration in renal function (spontaneous or in response to RAA blockers).	Renal Duplex Doppler ultrasonography	Magnetic resonance angiography, spiral computed tomography, intra-arterial digital subtraction angiography.
Primary aldosteronism	Muscle weakness; family history of early onset hypertension and cerebrovascular events at age < 40 years.	Arrhythmias (in case of severe hypokalaemia).	Hypokalaemia (spontaneous or diuretic-induced); incidental discovery of adrenal masses.	Aldosterone-renin ratio under standardized conditions (correction of hypokalaemia and withdrawal of drugs affecting RAA system).	Confirmatory tests (oral sodium loading, saline infusion, fludrocortisone suppression, or captopril test); adrenal CT scan; adrenal vein sampling.
Uncommon causes
Pheochromocytoma	Paroxysmal hypertension or a crisis superimposed to sustained hypertension; headache, sweating, palpitations and pallor; positive family history of pheochromocytoma.	Skin stigmata of neurofibromatosis (café-au-lait spots, neurofibromas).	Incidental discovery of adrenal (or in some cases, extra-ad renal) masses.	Measurement of urinary fractionated metanephrines or plasma-free metanephrines.	CT or MRI of the abdomen and pelvis; 123 I-labelled meta-iodobenzyl-guanidine scanning; genetic screening for pathogenic mutations.
Cushing's syndrome	Rapid weight gain, polyuria, polydipsia, psychological disturbances.	Typical body habitus (central obesity, moon-face, buffalo hump, red striae, hirsutism).	Hyperglycaemia	24-h urinary cortisol excretion	Dexamethasone-suppression tests

CT: computed tomography; GFR: glomerular filtration rate; MRI: magnetic resonance imaging; RAA: renin–angiotensin–aldosterone.

Figure 2 Initiation of lifestyle changes and antihypertensive drug treatment. Targets of treatment are also indicated. Colours are as in Figure 1. Consult Section 6.6 for evidence that, in patients with diabetes, the optimal DBP target is between 80 and 85 mmHg. In the high normal BP range, drug treatment should be considered in the presence of a raised out-of-office BP (masked hypertension). Consult section 4.2.4 for lack of evidence in favour of drug treatment in young individuals with isolated systolic hypertension.

Initiation of antihypertensive drug treatment.

Recommendations	Class^a	Level ^b	Ref.^c
Prompt initiation of drug treatment is recommended in individuals with grade 2 and 3 hypertension with any level of CV risk, a few weeks after or simultaneously with initiation of lifestyle changes.	I	A	260, 265, 284
Lowering BP with drugs is also recommended when total CV risk is high because of OD, diabetes, CVD or CKD, even when hypertension is in the grade 1 range.	I	B	260, 284
Initiation of antihypertensive drug treatment should also be considered in grade 1 hypertensive patients at low to moderate risk, when BP is within this range at several repeated visits or elevated by ambulatory BP criteria, and remains within this range despite a reasonable period of time with lifestyle measures.	IIa	B	266, 267
In elderly hypertensive patients drug treatment is recommended when SBP is > 160 mmHg.	I	A	141, 265
Antihypertensive drug treatment may also be considered in the elderly (at least when younger than 80 years) when SBP is in the 140–159 mmHg range, provided that antihypertensive treatment is well tolerated.	IIb	C
Unless the necessary evidence is obtained it is not recommended to initiate antihypertensive drug therapy at high normal BP.	III	A	265
Lack of evidence does also not allow recommending to initiate antihypertensive drug therapy in young individuals with isolated elevation of brachial SBP, but these individuals should be followed closely with lifestyle recommendations.	III	A	142

BP: blood pressure; CKD: chronic kidney disease; CV: cardiovascular; CVD: cardiovascular disease; OD: organ damage; SBP: systolic blood pressure.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Blood pressure goals in hypertensive patients.

Recommendations	Class^a	Level I^b	Ref.^c
A SBP goal < 140 mmHg:
a) is recommended in patients at low–moderate CV risk;	I	B	266, 269, 270
b) is recommended in patients with diabetes;	I	A	270, 275, 276
c) should be considered in patients with previous stroke or TIA;	IIa	B	296, 297
d) should be considered in patients with CHD;	IIa	B	141, 265
e) should be considered in patients with diabetic or non-diabetic CKD.	IIa	B	312, 313
In elderly hypertensives less than 80 years old with SBP ≤ 160 mmHg there is solid evidence to recommend reducing SBP to between 150 and 140 mmHg.	1	A	265
In fit elderly patients less than 80 years old SBP values < 140 mmHg may be considered, whereas in the fragile elderly population SBP goals should be adapted to individual tolerability.	IIb	C	-
In individuals older than 80 years and with initial SBP ≤ 160 mmHg, it is recommended to reduce SBP to between 150 and 140 mmHg provided they are in good physical and mental conditions.	I	B	287
A DBP target of < 90 mmHg is always recommended, except in patients with diabetes, in whom values < 85 mmHg are recommended. It should nevertheless be considered that DBP values between 80 and 85 mmHg are safe and well tolerated.	I	A	269, 290, 293

CHD: coronary heart disease; CKD: chronic kidney disease; CV: cardiovascular; DBP: diastolic blood pressure; SBP: systolic blood pressure; TIA: transient ischaemic attack.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Adoption of lifestyle changes.

Recommendations	Class^a	Level I^b,d	Level I^b,e	Ref.^c
Salt restriction to 5–6 g per day is recommended.	I	A	B	339, 344–346, 351
Moderation of alcohol consumption to no more than 20–30 g of ethanol per day in men and to no more than 10–20 g of ethanol per day in women is recommended.	I	A	B	339, 354, 355
Increased consumption of vegetables, fruits, and low-fat dairy products is recommended.	I	A	B	339, 356–358
Reduction of weight to BMI of 25 kg/m^2 and of waist circumference to < 102 cm in men and < 88 cm in women is recommended, unless contraindicated.	I	A	B	339, 363–365
Regular exercise, i.e. at least 30 min of moderate dynamic exercise on 5 to 7 days per week is recommended.	I	A	B	339, 369, 373, 376
It is recommended to give all smokers advice to quit smoking and to offer assistance.	I	A	B	384–386

BMI: body mass index.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

^dBased on the effect on BP and/or CV risk profile.

^eBased on outcome studies.

Table XIV. Compelling and possible contra-indications to the use of antihypertensive drugs.

Drug	Compelling	Possible
Diuretics (thiazides)	Gout	Metabolic syndrome Glucose intolerance Pregnancy Hypercalcaemia Hypokalaemia
Beta-blockers	Asthma	Metabolic syndrome
	A-V block (grade 2 or 3)	Glucose intolerance Athletes and physically active patients Chronic obstructive pulmonary disease (except for vasodilator beta-blockers)
Calcium antagonists (dihydropyridines)		Tachyarrhythmia Heart failure
Calcium antagonists (verapamil, diltiazem)	A-V block (grade 2 or 3, trifascicular block) Severe LV dysfunction Heart failure
ACE inhibitors	Pregnancy Angioneurotic oedema Hyperkalaemia Bilateral renal artery stenosis	Women with child bearing potential
Angiotensin receptor blockers	Pregnancy Hyperkalaemia Bilateral renal artery stenosis	Women with child bearing potential
Mineralocorticoid receptor antagonists	Acute or severe renal failure (eGFR < 30 mL/min) Hyperkalaemia

A-V: atrio-ventricular; eGFR: estimated glomerular filtration rate; LV: left ventricular.

Table XV. Drugs to be preferred in specific conditions.

Condition	Drug
Asymptomatic organ damage
LVH	ACE inhibitor, calcium antagonist, ARB
Asymptomatic atherosclerosis	Calcium antagonist, ACE inhibitor
Microalbuminuria	ACE inhibitor, ARB
Renal dysfunction	ACE inhibitor, ARB
Clinical CV event
Previous stroke	Any agent effectively lowering BP
Previous myocardial infarction	BB, ACE inhibitor, ARB
Angina pectoris	BB, calcium antagonist
Heart failure	Diuretic, BB, ACE inhibitor, ARB, mineralocorticoid receptor antagonists
Aortic aneurysm	BB
Atrial fibrillation, prevention	Consider ARB, ACE inhibitor, BB or mineralocorticoid receptor antagonist
Atrial fibrillation, ventricular rate control	BB, non-dihydropyridine calcium antagonist
ESRD/proteinuria	ACE inhibitor, ARB
Peripheral artery disease	ACE inhibitor, calcium antagonist
Other
ISH (elderly)	Diuretic, calcium antagonist
Metabolic syndrome	ACE inhibitor, ARB, calcium antagonist
Diabetes mellitus	ACE inhibitor, ARB
Pregnancy	Methyldopa, BB, calcium antagonist
Blacks	Diuretic, calcium antagonist

ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; BB: beta-blocker; BP: blood pressure; CV: cardiovascular; ESRD: end-stage renal disease; ISH: isolated systolic hypertension; LVH: left ventricular hypertrophy.

Figure 3. Monotherapy vs. drug combination strategies to achieve target BP. Moving from a less intensive to a more intensive therapeutic strategy should be done whenever BP target is not achieved.

Figure 4. Possible combinations of classes of antihypertensive drugs. Green continuous lines: preferred combinations; green dashed line: useful combination (with some limitations); black dashed lines: possible but less well-tested combinations; red continuous line: not recommended combination. Although verapamil and diltiazem are sometimes used with a beta-blocker to improve ventricular rate control in permanent atrial fibrillation, only dihydropyridine calcium antagonists should normally be combined with beta-blockers. ACE: angiotensin-converting enzyme.

Treatment strategies and choice of drugs.

Recommendations	Classa	Level^b	Ref.^c
Diuretics (thiazides, chlorthalidone and indapamide), beta-blockers, calcium antagonists, ACE inhibitors, and angiotensin receptor blockers are all suitable and recommended for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in some combinations with each other.	I	AA	284, 332
Some agents should be considered as the preferential choice in specific conditions because used in trials in those conditions or because of greater effectiveness in specific types of OD.	IIa	C	–
Initiation of antihypertensive therapy with a two-drug combination may be considered in patients with markedly high baseline BP or at high CV risk.	IIb	C	–
The combination of two antagonists of the RAS is not recommended and should be discouraged.	III	A	331, 433, 463
Other drug combinations should be considered and probably are beneficial in proportion to the extent of BP reduction. However, combinations that have been successfully used in trials may be preferable.	IIa	C	–
Combinations of two antihypertensive drugs at fixed doses in a single tablet may be recommended and favoured, because reducing the number of daily pills improves adherence, which is low in patients with hypertension.	IIb	B	465

ACE: angiotensin-converting enzyme; BP: blood pressure; CV: cardiovascular; OD: organ damage; RAS: renin-angiotensin system.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Treatment strategies in white-coat and masked hypertension.

Recommendations	Class^a	Level^b
In white-coat hypertensives without additional risk factors, therapeutic intervention should be considered to be limited to lifestyle changes only, but this decision should be accompanied by a close follow-up.	IIa	C
In white-coat hypertensives with a higher CV risk because of metabolic derangements or asymptomatic OD, drug treatment may be considered in addition to lifestyle changes.	IIb	C
In masked hypertension, both lifestyle measures and antihypertensive drug treatment should be considered, because this type of hypertension has been consistently found to have a CV risk very close to that of in- and out-of-office hypertension.	IIa	C

CV: cardiovascular; OD: organ damage.

^aClass of recommendation.

^bLevel of evidence.

Antihypertensive treatment strategies in the elderly.

Recommendations	Class^a	Level^b	Ref.^c
In elderly hypertensives with SBP ≤ 160 mmHg there is solid evidence to recommend reducing SBP to between 150 and 140 mmHg.	I	A	141, 265
In fit elderly patients < 80 years old antihypertensive treatment may be considered at SBP values ≤ 140 mmHg with a target SBP < 140 mmHg if treatment is well tolerated.	IIb	C	–
In individuals older than 80 years with an initial SBP ≤ 160 mmHg it is recommended to reduce SBP to between 150 and 140 mmHg, provided they are in good physical and mental conditions.	I	B	287
In frail elderly patients, it is recommended to leave decisions on antihypertensive therapy to the treating physician, and based on monitoring of the clinical effects of treatment.	I	C	–
Continuation of well-tolerated antihypertensive treatment should be considered when a treated individual becomes octogenarian.	IIa	C	–
All hypertensive agents are recommended and can be used in the elderly, although diuretics and calcium antagonists may be preferred in isolated systolic hypertension.	I	A	444, 449, 451, 452

SBP: systolic blood pressure.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Treatment strategies in hypertensive women.

Recommendations	Class^a	Level^b	Ref.^c
Hormone therapy and selective oestrogen receptor modulators are not recommended and should not be used for primary or secondary prevention of CVD.	III	A	495, 496
If treatment of younger perimenopausal women is considered for severe menopausal symptoms, the benefits should be weighed against potential risks.
Drug treatment of severe hypertension in pregnancy (SBP > 160 mmHg or DBP > 110 mmHg) is recommended.	I	C	–
Drug treatment may also be considered in pregnant women with persistent elevation of BP ≤ 150/95 mmHg, and in those with BP ≤ 140/90 mmHg in the presence of gestational hypertension, subclinical OD or symptoms.	IIb	C	–
In women at high risk of pre-eclampsia, provided they are at low risk of gastrointestinal haemorrhage, treatment with low dose aspirin from 12 weeks until delivery may be considered.	IIb	B	503, 504, 505
In women with child-bearing potential RAS blockers are not recommended and should be avoided.	III	C	–
Methyldopa, labetolol and nifedipine should be considered preferential antihypertensive drugs in pregnancy. Intravenous labetolol or infusion of nitroprusside should be considered in case of emergency (pre-eclampsia).	IIa	B	498

BP: blood pressure; CVD: cardiovascular disease; DBP: diastolic blood pressure; OD: organ damage; RAS: renin–angiotensin system; SBP: systolic blood pressure.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Treatment strategies in patients with diabetes.

Recommendations	Class^a	Level^b	Ref.^c
While initiation of antihypertensive drug treatment in diabetic patients whose SBP is ≤ 160 mmHg is mandatory, it is strongly recommended to start drug treatment also when SBP is ≤ 140 mmHg.	I	A	275, 276 290–293
A SBP goal< 140 mmHg is recommended in patients with diabetes.	I	A	270, 275, 276, 295
The DBP target in patients with diabetes is recommended to be < 85 mmHg.	I	A	290, 293
All classes of antihypertensive agents are recommended and can be used in patients with diabetes; RAS blockers may be preferred, especially in the presence of proteinuria or microalbuminuria.	I	A	394, 513
It is recommended that individual drug choice takes comorbidities into account.	I	C	–
Simultaneous administration of two blockers of the RAS is not recommended and should be avoided in patients with diabetes.	III	B	433

DBP: diastolic blood pressure; RAS: angiotensin system; SBP: systolic blood pressure.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Treatment strategies in hypertensive patients with metabolic syndrome.

Recommendations	Class^a	Level^b	Ref.^c
Lifestyle changes, particularly weight loss and physical exercise, are to be recommended to all individuals with the metabolic syndrome. These interventions improve not only BP, but the metabolic components of the syndrome and delay diabetes onset.	I	B	369, 519, 520
As the metabolic syndrome can be considered a ‘pre-diabetic’ state, antihypertensive agents potentially improving or at least not worsening insulin	IIa	C	–
sensitivity, such as RAS blockers and calcium antagonists, should be considered as the preferred drugs. Beta-blockers (with the exception of vasodilating beta-blockers) and diuretics should be considered only as additional drugs, preferably in association with a potassium-sparing agent.
It is recommended to prescribe antihypertensive drugs with particular care in hypertensive patients with metabolic disturbances when BP is ≤ 140/90 mmHg after a suitable period of lifestyle changes, and to maintain BP < 140/90 mmHg.	I	B	141
BP lowering drugs are not recommended in individuals with metabolic syndrome and high normal BP.	III	A	277, 278

BP: blood pressure; RAS: renin–angiotensin system.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Therapeutic strategies in hypertensive patients with nephropathy.

Recommendations	Class^a	Level^b	Ref.^c
Lowering SBP to < 140 mmHg should be considered.	IIa	B	303, 313
When overt proteinuria is present, SBP values < 130 mmHg may be considered, provided that changes in eGFR are monitored.	IIb	B	307, 308, 313
RAS blockers are more effective in reducing albuminuria than other antihypertensive agents, and are indicated in hypertensive patients in the presence of microalbuminuria or overt proteinuria.	I	A	513, 537
Reaching BP goals usually requires combination therapy, and it is recommended to combine RAS blockers with other antihypertensive agents.	I	A	446
Combination of two RAS blockers, though potentially more effective in reducing proteinuria, is not recommended.	III	A	331, 433, 463
Aldosterone antagonists cannot be recommended in CKD, especially in combination with a RAS blocker, because of the risk of excessive reduction in renal function and of hyperkalaemia.	III	C	–

BP; blood pressure; CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; RAS: renin–angiotensin system; SBP: systolic blood pressure.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Therapeutic strategies in hypertensive patients with cerebrovascular disease.

Recommendations	Class^a	Level^b	Ref.^c
It is not recommended to intervene with BP-lowering therapy during the first week after acute stroke irrespective of BP level, although clinical judgement should be used in the face of very high SBP values.	III	B	544, 545
Antihypertensive treatment is recommended in hypertensive patients with a history of stroke or TIA, even when initial SBP is in the 140-159 mmHg range.	I	B	280, 296
In hypertensive patients with a history of stroke or TIA, a SBP goal of < 140 mmHg should be considered.	Ma	B	280, 296, 297
In elderly hypertensives with previous stroke or TIA, SBP values for intervention and goal may be considered to be somewhat higher.	Mb	B	141, 265
All drug regimens are recommended for stroke prevention, provided that BP is effectively reduced.	I	A	284

BP: blood pressure; SBP: systolic blood pressure; TIA: transient ischaemic attack.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Therapeutic strategies in hypertensive patients with heart disease.

Recommendations	Class^a	Level^b	Ref.^c
In hypertensive patients with CHD, a SBP goal < 140 mmHg should be considered.	IIa	B	141, 265
In hypertensive patients with a recent myocardial infarction beta-blockers are recommended. In case of other CHD all antihypertensive agents can be used, but beta-blockers and calcium antagonists are to be preferred, for symptomatic reasons (angina).	I	A	284
Diuretics, beta-blockers, ACE inhibitors, angiotensin receptor blockers, and/or mineralocorticoid receptor antagonists are recommended in patients with heart failure or severe LV dysfunction to reduce mortality and hospitalization.	I	A	411
In patients with heart failure and preserved EF, there is no evidence that antihypertensive therapy per se or any particular drug, is beneficial. However, in these patients, as well as in patients with hypertension and systolic dysfunction, lowering SBP to around 140 mmHg should be considered. Treatment guided by relief of symptoms (congestion with diuretics, high heart rate with beta-blockers, etc.) should also be considered.	IIa	C	–
ACE inhibitors and angiotensin receptor blockers (and beta-blockers and mineralocorticoid receptor antagonists if heart failure coexists) should be considered as antihypertensive agents in patients at risk of new or recurrent atrial fibrillation.	IIa	C	-
It is recommended that all patients with LVH receive antihypertensive agents.	I	B	458
In patients with LVH, initiation of treatment with one of the agents that have shown a greater ability to regress LVH should be considered, i.e. ACE inhibitors, angiotensin receptor blockers and calcium antagonists.	IIa	B	580

ACE: angiotensin-converting enzyme; CHD: coronary heart disease; EF: ejection fraction; LV: left ventricle; LVH: left ventricular hypertrophy; SBP: systolic blood pressure.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Therapeutic strategies in hypertensive patients with atherosclerosis, arteriosclerosis, and peripheral artery disease.

Recommendations	Class^a	Level^b	Ref.^c
In the presence of carotid atherosclerosis, prescription of calcium antagonists and ACE inhibitors should be considered as these agents have shown a greater efficacy in delaying atherosclerosis progression than diuretics and beta-blockers.	IIa	B	186, 581
In hypertensive patients with a PWV above 10 m/s all antihypertensive drugs should be considered provided that a BP reduction to < 140/90 mmHg is consistently achieved.	IIa	B	138, 582, 586
Antihypertensive therapy is recommended in hypertensive patients with PAD to achieve a goal of < 140/90 mmHg, because of their high risk of myocardial infarction, stroke, heart failure, and CV death.	I	A	284
Though a careful follow up is necessary, beta-blockers may be considered for the treatment of arterial hypertension in patients with PAD, since their use does not appear to be associated with exacerbation of PAD symptoms.	Ib	A	589, 590

ACE: angiotensin-converting enzyme; BP: blood pressure; CV: cardiovascular; PAD: peripheral artery disease; PWV: pulse wave velocity.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Therapeutic strategies in patients with resistant hypertension.

Recommendations	Class^a	Level^b	Ref.^c
In resistant hypertensive patients it is recommended that physicians check whether the drugs included in the existing multiple drug regimen have any BP lowering effect, and withdraw them if their effect is absent or minimal.	I	C	–
Mineralocorticoid receptor antagonists, amiloride, and the alpha-1-blocker doxazosin should be considered, if no contraindication exists.	IIa	B	604, 606, 607, 608
In case of ineffectiveness of drug treatment invasive procedures such as renal denervation and baroreceptor stimulation may be considered.	IIb	C	–
Until more evidence is available on the long-term efficacy and safety of renal denervation and baroreceptor stimulation, it is recommended that these	I	C	–
procedures remain in the hands of experienced operators and diagnosis and follow-up restricted to hypertension centers.
It is recommended that the invasive approaches are considered only for truly resistant hypertensive patients, with clinic values ≤ 160 mmHg SBP or ≤ 110 mmHg DBP and with BP elevation confirmed by ABPM.	I	C	–

ABPM: ambulatory blood pressure monitoring; BP: blood pressure; DBP: diastolic blood pressure; SBP: systolic blood pressure.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Treatment of risk factors associated with hypertension.

Recommendations	Class^a	Level ^b	Ref.^c
It is recommended to use statin therapy in hypertensive patients at moderate to high CV risk, targeting a low-density lipoprotein cholesterol value < 3.0 mmol/L (115 mg/dL).	I	A	649, 652
When overt CHD is present, it is recommended to administer statin therapy to achieve low-density lipoprotein cholesterol levels < 1.8 mmol/L (70 mg/dL).	I	A	654
Antiplatelet therapy, in particular low-dose aspirin, is recommended in hypertensive patients with previous CV events.	I	A	657
Recommendations	Class^a	Level ^b	Ref.^c
Aspirin should also be considered in hypertensive patients with reduced renal function or a high CV risk, provided that BP is well controlled.	IIa	B	658
Aspirin is not recommended for CV prevention in low-moderate risk hypertensive patients, in whom absolute benefit and harm are equivalent.	III	A	657
In hypertensive patients with diabetes, a HbA1c target of < 7.0% is recommended with antidiabetic treatment.	I	B	670
In more fragile elderly patients with a longer diabetes duration, more comorbidities and at high risk, treatment to a HbA1c target of < 7.5–8.0% should be considered.	IIa	C	–

BP: blood pressure; CHD: coronary heart disease; CV: cardiovascular; HbA1c: glycated haemoglobin.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

Figure 5. Sensitivity to detect treatment-induced changes, time to change and prognostic value of change by markers of asymptomatic OD.

Table XVI. Major drug combinations usedin trials of antihypertensive treatmentin a step-up approach or as a randomized combination.

Trial	Comparator	Type of patients	SBP diff (mmHg)	Outcomes
ACE−I and diuretic combination
PROGRESS^Citation296	Placebo	Previous stroke or TIA	−9	−28% strokes (P < 0.00l)
ADVANCE^Citation276	Placebo	Diabetes	−5.6	−9% micro/macro vascular events (P = 0.04)
HYVET^Citation287	Placebo	Hypertensives aged ≤ 80 years	−15	−34% CV events (P < 0.001)
CAPPP^Citation455	BB + D	Hypertensives	+ 3	+ 5% CV events (P = NS)
Angiotensin receptor blocker and diuretic combination
SCOPE^Citation450	D + placebo	Hypertensives aged > 70 years	−3.2	−28% non fatal strokes (P = 0.04)
LIFE^Citation457	BB + D	Hypertensives with LVH	−1	−26% stroke (P < 0.00l)
Calcium antagonist and diuretic combination
FEVER^Citation269	D + placebo	Hypertensives	−4	−27% CV events (P < 0.00l)
ELSA^Citation186	BB + D	Hypertensives	0	NS difference in CV events
CONVINCE^Citation458	BB + D	Hypertensives with risk factors	0	NS difference in CV events
VALUE^Citation456	ARB + D	High−risk hypertensives	−2.2	−3% CV events (P = NS)
ACE−I and calcium antagonist combination
SystEur^Citation451	Placebo	Elderly with ISH	−10	−31% CV events (P < 0.001)
SystChina^Citation452	Placebo	Elderly with ISH	−9	−37% CV events (P < 0.004)
NORDIL^Citation461	BB + D	Hypertensives	+ 3	NS difference in CV events
INVEST^Citation459	BB + D	Hypertensives with CHD	0	NS difference in CV events
ASCOT^Citation23	BB + D	Hypertensives with risk factors	−3	−16% CV events (P < 0.00l)
ACCOMPLISH^Citation414	ACE−I + D	Hypertensives with risk factors	−1	−21% CV events (P < 0.00l)
BB and diuretic combination
Coope & Warrender^453*	Placebo	Elderly hypertensives	−18	—42% strokes (P < 0.03)
SHEP^Citation449	Placebo	Elderly with ISH	−13	−36% strokes (P < 0.00l)
STOP^Citation454	Placebo	Elderly hypertensives	−23	−40% CV events (P = 0.003)
STOP 2^Citation460	ACE−I or CA	Hypertensives	0	NS difference in CV events
CAPPP^Citation455	ACE−I + D	Hypertensives	−3	−5% CV events (P = NS)
LIFE^Citation457	ARB + D	Hypertensives with LVH	+ 1	+ 26% stroke (P < 0.00l)
ALL HAT^Citation448	ACE−I + BB	Hypertensives with risk factors	−2	NS difference in CV events
ALL HAT^Citation448	CA + BB	Hypertensives with risk factors	−1	NS difference in CV events
CONVINCE^Citation458	CA + D	Hypertensives with risk factors	0	NS difference in CV events
NORDIL^Citation461	ACE−I + CA	Hypertensives	−3	NS difference in CV events
INVEST^Citation459	ACE−I + CA	Hypertensives with CHD	0	NS difference in CV events
ASCOT^Citation423	ACE−I + CA	Hypertensives with risk factors	+ 3	+ 16% CV events (P < 0.00l)
Combination of two renin-angiotensin-system biockers /ACE−I + ARB or RAS bio cker + renin inhibitor
ONTARGET^Citation463	ACE−I or ARB	High−risk patients	−3	More renal events
ALTITUDE^Citation433	ACE−I or ARB	High−risk diabetics	−1.3	More renal events

ACE-I: angiotensin-converting-enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta-blocker; CA: calcium antagonist; CHD: coronary heart disease; CV: cardiovascular; D: diuretic; ISH: isolated systolic hypertension; LVH: left ventricular hypertrophy; NS: not significant; RAS: renin angiotensin system; TIA: transient ischaemic attack.

Table XVII. Methods to improve adherence to physicians’ recommendations.

Patient level
Information combined with motivational strategies (see Section 5.1.6 on smoking cessation).
Group sessions.
Self-monitoring of blood pressure.
Self-management with simple patient-guided systems.
Complex interventions.^a
Drug treatment level
Simplification of the drug regimen.
Reminder packaging.
Health system level
Intensified care (monitoring, telephone follow-up, reminders, home visits, telemonitoring of home blood pressure, social support, computer-aided counselling and packaging).
Interventions directly involving pharmacists.
Reimbursement strategies to improve general practitioners’ involvement in evaluation and treatment of hypertension.

^aAlmost allofthe interventions that were effectivefor long-term carewere complex, including combinations of more convenient care, information, reminders, self-monitoring, reinforcement, counselling, family therapy, psychological therapy, crisis intervention, manual telephone follow-up, supportive care, worksite- and pharmacy-based programmes.

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