n i y c n e u q e r F Blood pressure Fig. 6.1 Distribution of BP in any population: the cut-off for de \201 ning \200\230 high \200\231 BP is arbitrary. De \201 nition Perhaps the most useful de \201 nition is: Hypertension is a level of blood pressure which places an individual at increased risk of c ardiovascular events and, when treated, results in more bene \201 t than harm. SBP, pulse pressure, and CV risk SBP \200 Historically, DBP was thought the best predictor of CV disease. \200 It is now clear that SBP has a continuous independent relationship with stroke and IHD risk. It can be dif \201 cult to get SBP to target, particularly in the elderly. Pulse pressure (PP) and risk \200 PP is SBP minus DBP. \200 A wide PP more accurately p redicts adverse CV outcome than SBP or DBP. PP appears to be a marker of arterial stiffness. \200 PP may identify those with SBP at p articularly high CV risk. \200 At present, the majority of outcome data from clinical tri als is for SBP and DBP, so the major guidelines are based on these, rather than on PP. CHAPTER 6 Hypertension 452 Pathogenesis: general Introduction The great apes do not get i BP, nor do present-day hunte r-gatherer popu- lations (with a similar diet and lifestyle to that of our ancestors). It a ppears that there are important factors within our environment and diet that pre- dispose t o hypertension. Genetic in \202 uences are important but insuf \201 cient in isolation. The \201 nal common pathway in chronic i BP is i OH systemic vascular resistance (SVR). T he earliest event in the development of i BP is usually a rise in cardiac output (CO). i CO causes an increase in wall:lumen ratio in resistance vessels (to normalize wall stress). T his leads to a sustained rise in SVR and causes chronic i BP. CO is usually normal in those with established hypertension. BP = cardiac output (CO) x systemic vascular resistance (SVR) Central role of the kidney \200 Sodium excretion depends on renal perfusion pressure (the Guyton hypothesis). So i renal perfusion l pressure natriuresis. In i BP, the curve descri bing this relationship is pushed to the right (see Fig. 6.2). \200 In most people, the re nal pressure natriuresis curve is steep (a small increase in BP l large i in salt excretion). If this curve is shallower, BP will vary more widely with salt intake. This \200\230 salt-sensitive \200\231 i BP occurs more commonly in black patients and in CKD. Monogenic forms of i BP (rare!) suggest tubular ion transportation mechanisms are important mediators of blood pressure control. n o i t e r c x e m u d o S i Afferent arteriolar pressure Fig. 6.2 In the normotensive individual, salt balance is maintained at a normal BP. The slo pe of the curve is very steep such that dietary salt loading does not signi \201 cantly al ter BP. In hypertensive individuals, the curve is shifted to the right, though it remains p arallel. Thus, on a normal sodium diet, salt balance is maintained but at a higher BP. In s alt-sensitive individuals, the rightward shift is accompanied by a depression of the slope (not shown). Thus, not only is the BP set point on a normal diet elevated, but the BP also increases in response to dietary salt loading. PATHOGENESIS: GENERAL 453 Salt intake and blood pressure \200 There is a large body of evidence supporting the role of high salt intake in the development of i BP. Genetic disorders associated with i BP often affect salt regulation. \200 A high habitual salt intake is important for the development of the increase in BP with age. The effects of salt appear dose-dependent. \200 A key study, the Intersalt study, found t hat populations with a low intake of dietary sodium have a low prevalence of i BP. i BP is seen mainly in societies with a salt intake > 6g per day. Modest reduction in salt intake for people on a typical western diet results in a BP drop o f 5.3/3.7mmHg in hypertensive patients and 1.9/1.1mmHg in normotensives. Were salt intake to be reduced over many years, the population bene \201 ts would be substantial. The recommended intake is <6g/day salt. \200 The UK has led the way in reducing the salt content of food through public health programs and engagement with food manufacturers. The major challenge for consumers is to be aware of the amount of \200\230 hidden \200\231 salt in food. New labeling will hopefully go some way to help them to identify healthier food options. Endothelial dysfunction and nitric oxide i BP is associated with impaired endothelium-depen dent relaxation of the vessel wall. A number of factors in \202 uence endothelial function : \200 Nitric oxide (NO): NO l relaxation of vascular smooth muscle. Released by endothelium in response to shear str ess (i.e. blood \202 ow). Endogenous NO synthase (eNOS) l continuous normal basal release. Inducible iNOS l high concentrations of NO in response to in \202 ammatory cytoki nes. d NO has been reported in hypertensive patients (+ their offspring). Oxidative stress: free radicals scavenge NO, forming potentially toxic by-products. Radical s themselves (such as superoxide, O 2 \200\223 ) are potent vasoconstrictors. Prostaglandins: prostacyclin (PGI 2 ) is released by endothelial cells in response to shear stress and has a synergistic effect on tone with NO. Angiotensin II: a vasoconstrictor, also contributes to free radical generation and to endothelin release. Endothelins: potent vasoconstrictors, opposing the actions of NO. Also cause renal Na + ret ention, i aldosterone, vascular smooth muscle cell proliferation, cardiac hypertrophy, and \201 brosis. Their role in the pathogenesis of i BP is unclear. CHAPTER 6 Hypertension 454 Pathogenesis: genetics, arterial stiffness, and SNS Genetics Inheritance is not Mendelian. No one gene is responsible. Larger collabo- rative studies are providing information on sus ceptibility genes. Blood pressure levels are similar amongst close relatives (even those with \200\230 normal \200\231 range BP), suggesting alleles on several different genes may have an effect on B P. Rare monogenic causes of i BP have been identi \201 ed, using linkage analysis in affected families (see Box 6.1). Defects in these genes may also be important in essential hyperten sion (gene defects coding the B and G subunits of the epithelial Na + channel (linked to Li ddle \200\231 s syndrome) are associated with BP variations in the general population). Research focus has been on likely culprit genes (esp. the angiotensino- gen gene) and is now looking at genome-wide associations. Genes that have been associated with essential i BP include: ACE polymorphisms (I/I and I/D phenotypes associate with salt-sensitive hypertension). A -adducin polymorphisms \200\224 a cytoskeletal protein which regulates ion transportatio n in the renal tubule. Polymorphisms may relate to salt sensitivity, diuretic sensitivity, and essential hypertension. 11 B -hydroxysteroid dehydrogenase (GG phenotype correlates with salt sensitivity). AT-1 receptor gene \200\224 in experimental studies, AT-1a +/+ mice have higher blood pres sures than \200\223 / \200\223 mice. Clinical relevance unknown. Box 6.1 Rare single-gene causes of hypertension \200 Liddle \200\231 s syndrome: mutatio ns affect the epithelial sodium channel (ENaC). Autosomal dominant, with i BP characterized by d renin, d aldosterone, and d K + ( b p. 801). Glucocorticoid-remediable aldosteronism ( b p. 478). \200 Syndrome of apparent mineraloco rticoid excess ( b p. 480). \200 Pregnancy-associated hypertension: a gene defect l parti al activation of the mineralocorticoid receptor by progesterone (rare). \200 Phaeochromocytoma: may occ ur with one of the following: Multiple endocrine neoplasia type 2A: mutations in the RET proto-oncogene. Autosomal dominant. Phaeochromocytoma, medullary thyroid carcinoma, and hyp erparathyroidism. von Hippel \200\223 Lindau disease ( b p. 745). \200 Neuro \201 bromatosis type 1: muta tions in the NF1 tumor suppressor gene, autosomal dominant. Presents with phaeochromocytoma s, multiple neuro \201 bromas, caf -au-lait spots, Lisch nodules of the iris. PATHOGENESIS: GENETICS, ARTERIAL STIFFNESS, AND SNS 455 Arterial stiffness Arterial pressure depends in part on the compliance of conduit arteries. Stiff arteries are less able to dampen a surge in pressure during systole, so systolic pre ssure is higher. A stiffer artery will also conduct a pulse wave more rapidly. Normally, th e pulse wave is re \202 ected back from the small vessels, arriving back at the heart duri ng diastole. If conducted more rap- idly, the re \202 ected pulse wave may reach the heart during systole, further i systolic pressure and d diastolic pressure. Coronary artery perf usion, which occurs predominantly during diastole, may be affected. Commoner causes of reduced compliance (or i stiffness) include: \200 Ageing: loss of elas tin, calci \201 cation of arterial walls, lipid deposition, and defective endothelial function all contribute. Diabetes: i arterial stiffness is accelerated (even if i BP is absent) s to non-enzymatic g lycosylation of connective tissue, high insulin levels 9 activation of the sympathetic nerv ous system. CKD, esp. ESRD: oxidant stress, impaired endothelial function, abnormal lipid pro \201 le, calci \201 cation of the arterial wall (exacerbated by disord ered mineral metabolism), and a variety of putative uraemic toxins all contribute ( b p. 21 2). 1 Increased arterial stiffness and pulse wave velocity are independent pre- dictors of all- cause mortality and CV morbidity and mortality in patients with i BP. Sympathetic nervous system (SNS) There has been considerable recent interest in the role of the SNS in i BP, with the development of techniques to reduce sympathetic activity. These include renal denervation with radiofrequency energy and baroreceptor activation therapy ( b p. 514). Activation of the SNS is clearly linked with acute i BP \200\224 chronic acti- vation may have a role in the genesis of long-term i BP in those with a genetic predisposition. SNS activation causes: i in stroke volume (via A -1 and -2 receptors). \200 i in heart rate (via B -1 receptors) . \200 i in systemic vascular resistance (via A -1 receptors). \200 Activation of the R AS (via B -1 receptor-mediated renin release). CHAPTER 6 Hypertension 456 Pathogenesis: RAS and other factors The renin \200\223angiotensin system (RAS) Plays a cent ral role in salt and water homeostasis, and 6 BP control. An impor- tant therapeutic target (ACE-I, ARBs, renin inhibitors) ( b pp. 508 \200\223511). Granular cells in the juxtaglomerular apparatus synthesize and release renin. Renin convert s inactive angiotensinogen into angiotensin I, which, in turn, is converted by ACE in the l ungs to active angiotensin II (A2). A2 binds two receptors AT-1 and -2 ( b p. 510). Renin r elease is mediated by: \200 d afferent arteriolar (i.e. renal perfusion) pressure of any cause. \200 Sympathetic nervous system activation (granular cell B -1 receptors). \200 d Na + delivery to the distal tubule (sensed by the macula densa). \200 Prostacyclin, ACT H. Causes of i renin \200 Sympathetic stimulation. \200 Renal artery stenosis. \200 Rena l cell carcinoma. \200 Benign reninoma (very rare). \200 Other renin-secreting malignan cies (also very rare). \200 Many antihypertensives, including CCBs and diuretics. 2 Many patients with essential hypertension have i plasma renin levels not related to any o f the listed causes, nor of any therapeutic relevance. Angiotensin Circulating A2 binds vascular receptors, but locally released A2 works at tissu e level in a paracrine fashion. Tissue concentrations do not correlate with systemic levels but may correlate better with disease pathogenesis. Actions of angiotensin II \200 Arteriolar vasoconstriction (and venular constriction to a lesser extent). \200 Efferent renal arteriolar vasoconstriction. \200 Aldosterone secr etion. \200 Adrenaline (epinephrine) release. \200 Smooth muscle hypertrophy. \200 In creased reabsorption of sodium in PCT. \200 Inhibits renin release (negative feedback loo p). \200 Renal mesangial cell growth and matrix expansion. \200 Myocardial growth and m atrix expansion. \200 Stimulates thirst and ADH release. Most effects are mediated by the angiotensin type 1 (AT-1) receptor. The role of AT-2 receptors remains unclear, but ligand binding may regulate vasodilator, proliferative, and apoptotic effects of A2. PATHOGENESIS: RAS AND OTHER FACTORS 457 Aldosterone Aldosterone synthesis occurs mainly in the zona glomerulosa of the adre- nal co rtex and is tightly regulated by the RAS and electrolyte homeostasis ( i K + or d Na + inta ke l aldosterone synthesis). Aldosterone acts at the collecting duct to promote Na + retention and K + excretion ( b p. 930). Cortisol also activates the mineralocor- ticoid receptor \200\224 so aldosterone-sen sitive tissues contain high levels of 11 B -hydroxysteroid dehydrogenase type 2 (converts c ortisol l cortisone, which is incapable of activating the receptor), protecting the mineral ocor- ticoid receptor from states of high circulating cortisol. Extrarenal actions of aldosterone \200 Paracrine action in non-epithelial tissues (brain, heart, epithelium). \200 Associated with vascular in \202 ammation and cardiac \201 b rosis. The same may be true in non-vascular tissues. Activates pro- \201 brotic and growth factors in several tissues (including the kidney). Other factors \200 There is much redundancy in the control of BP. Many neuroendocrine sys tems contribute to it in overlapping and interlocking ways \200\224 and any (or all) of th ese may lead to abnormal BP. Insulin resistance has a clear relationship with i BP: Fasting insulin and glucose levels correlate with BP in insulin-resistant patients. Relatives of those with i BP are more likely to have insulin resistance. Insulin resistance predicts the subsequent development of i BP. \200 Mechanisms may inclu de SNS activation and Na + retention. Natriuretic peptides, including: ANP (atrial natriuretic peptide). Released by atrial tissue in response to stretch, i.e. volume overload. BNP (brain natriuretic peptide). First discovered in the brain but synthesized and secreted by ventricular myocardium. \200 CNP (C-type) and DNP (Dendroaspi s). More recently discovered. Relevance not yet clear (DNP was \201 rst discovered in the venom of the gree n mamba snake. Its subsequent detection in the plasma of humans is of uncertain signi \201 cance. It may play a part in the diuresis associated with subarachnoid hemorrhage). \200 Urodilatin. Similar structure to ANP but con \201 ned to the kidney. Synthesized in distal tubular cells, causing natriuresis. The natriuretic peptides are secreted in response to volume overload, leading to a compensa tory natriuretic effect. Other effects include vaso- dilation, modulation of vascular smoot h muscle function, and control of the RAS system. Their role in the pathogenesis of i BP is less clear. In experimental studies, defects in natriuretic peptide production appear to c ause salt-sensitive i BP. CHAPTER 6 Hypertension 458 BP measurement Clinic readings \200 Gold standard is mercury sphygmanometer. However, env ironmental concerns about mercury contamination have led to its gradual disappearance from clinical pr actice. Substitutes (aneroid sphygmanometers or oscillometric automated devices) are now preferred. Semi-automated devices may not measure BP accurately in some clinical conditions, e.g. atri al \201 brillation. Palpate the radial/brachial pulse before measuring, and, if irregular , measure BP, using a manual device. Validation and maintenance are vital: for a list of approved apparatus, see M http://www.bh soc.org for British Hypertension Society or M http://www.heart.org for American Heart Assoc iation. Examiner s technique is vital 1 Even a relatively small error in BP measurement could resul t in inap- propriate under- or overtreatment. \200 Standing BP should be recorded, esp. d uring the initial assessment of elderly or diabetic patients. Measure in both arms. If there is a signi \201 cant difference (>20mmHg), then repeat. Mea sure subsequently in the arm with the higher value. Place cuff 1 \200\223 2cm above the antecubital fossa. \200 Select appropriate cuff size . Cuff bladder width should be 40% and length 80% of arm. The standard adult bladder is 12 x 26cm (although some consider 12 x 35c m standard). \200 Cuff too large l underestimation. \200 Cuff too small l overestimatio n. In \202 ate cuff whilst palpating the radial artery to estimate SBP. In \202 ate cuff to 30mmHg above estimated SBP. De \202 ate at 2mmHg/s, listening to Korotkoff phase I (appearance) for SBP and phase V (disappearance) for DBP. If phase V goes to zero, use phase IV (muf \202 i ng). Take two measurements 1 \200\223 2min apart, and read to the nearest 2mmHg (round off upwards). Document the time of measurement in relation to tablets. \200 Do not round up or down to preconceived values (observer \200\231 s prejudice). Ambulatory BP monitoring (ABPM) Now recommended in the UK by the National Institute for Hea lth and Care Excellence (NICE) for the diagnosis of i BP (daytime). Daytime ambulatory BP c orrelates better with target organ damage (TOD) than clinic BP and provides a more accurate diagnosis of i BP. Day, night, and 24-hour BP measurements are recorded and are usually lo wer than clinic measurements (see Table 6.1 and Fig. 6.3). The patient should refrain from strenuous exercise and straightening their arm during measurement (tricky if driving) and s hould keep a concomitant diary, e.g. sleep times. For an accurate result, two measurements per hour during the day, with a BP MEASUREMENT 459 minimum of 14 measurements, are required. Several limitations, including cost, lack of outc ome data for patients already on treatment, and accept- ability to patients, still limit us e. Indications for ABPM \200 If clinic BP is >140/90mmHg or higher. \200 Possible white co at effect or white coat hypertension. \200 Resistant i BP. \200 When BP unusually varia ble. \200 To identify nocturnal hypertension. \200 Symptoms suggestive of hypotension. \200 Diagnosis and treatment of hypertension in pregnancy. ABPM readings and interpretation Table 6.1 ABPM readings at differing periods Normal Abnormal Daytime < 135/85 > 140/90 Night-time < 120/70 > 125/75 24 hours < 130/80 > 135/85 Systolic blood pressure Blood pressure threshold while awake, 140/90mmHg Blood pressure threshold while asleep, 125/75mmHg Diastolic blood pressure 240 200 ) g H m m 160 ( e r u s s e r p 120 80 d o o B 40 l Sleep 0 12 13 14 15 16 17 18 19 20 21 22 23 24 01 02 03 04 05 06 07 08 09 10 11 12 Time (hours) Fig. 6.3 Example of variation in daytime and night-time BP. Look for the following characteristics: \200 Nocturnal dipping: mean wake systolic BP fal ls by at least 10% during sleep. \200\230 Super \200\231 dipping (20 \200\223 30%) is associated with neurological sequelae. Non-dipping, or reverse dipping, is associated with increased CV mortality and T OD. Masked i BP: normal clinic BP but elevated ABPM. Associated with higher prevalence of TOD. CHAPTER 6 Hypertension 460 White coat hypertension: elevated clinic BP, with normal ABPM and no evidence of TOD. Increased prevalence with i age, milder hypertension (10 \200\223 30% grade 1, <10% grades 2 and 3). Associated with increased CV risk. In hypertensive patie nts, known as \200\230 white coat effect \200\231 . Target ABPM for treated patients is < 135/85 aged under 80, <145/85 aged over 80. Home Can be used as an alternative to ABPM for the diagnosis of i BP. When con \201 rming hypertension using home BP \200 Take two consecutive measurements fo r each BP recording, at least 1min apart. Record BP twice daily (morning and evening). \200 Take readings for at least 4 days (idea lly, 7 days). \200 Discard the \201 rst day \200\231 s measurements. \200 Use the av erage value of all the remaining measurements. When treating hypertension using home BP \200 Management of BP, according to home measure ments, in individuals already receiving treatment is not backed by robust evidence. Home BP monitors are often inaccurate. The British Hypertension Society has a list of valid ated machines on their website (M http:// www.bhsoc.org ). Patients are more likely to reach target BP with home BP monitoring but will need the same number of tablets to do so. It can be very helpful to involve patients in their own management. \200 Helpful in those with white coat effect where the target BP is: Aged below 80 <135/85mmHg. \200 Aged over 80 <145/85mmHg. Blood pressure variability \200 A recent series of analyzes have recently been published, showing that excessive variability in BP is an independent risk factor for CVD. Variability in SBP is a strong predictor of stroke (independent of mean SBP). In treated i BP, this variability is associated with a higher risk of vascular events. BP variability is measured as the standard deviation of mean BP. \200 Not clear if causat ion, or marker, of vascular disease. \200 The different classes of antihypertensive agent vary in their capacity to in \202 uence this BP variability. CCBs and thiazide-like diuretics are the most effective at reducing variability. Older and black patients are more likely to have i SBP variability. BP MEASUREMENT 461 CHAPTER 6 Hypertension 462 Clinical assessment There are four fundamental questions to consider: \200 Is this sustai ned hypertension? \200 Is this primary or secondary hypertension? \200 Are there other cardiovascular risk factors? \200 Is there target organ disease? Management of an individual patient will depend on these factors. History and examination \200 Duration of elevated BP. Previous monitoring, treatment, and control. \200 Previous drug treatment and side effects. \200 Contraindications to spec i \201 c drugs, e.g. bronchospasm. \200 Family history: i BP, stroke, diabetes, i lipids , renal disease, premature IHD. Previous history of pre-eclampsia or hypertension during pregnancy? \200 Is this primary or secondary hypertension ( b p. 474)? The following may suggest a secondary cause: \200 Young age ( < 30 years, esp. if no FH and Caucasian). \200 Sudden-onset hypertension. \200 Presents as malignant hypertension ( b p. 518). \200 Acute rise with previously stable BP control. \200 Severe or \200\230 resistant \200\231 ( \211 3 drugs) hypertension. \200 Other diagnostic clues ( b p. 475)? Other contributory factors? Other cardiovascular risk factors? \200 Drugs (NSAIDs, decong estants, cocaine, amphetamines). \200 Obesity. \200 Excess alcohol. \200 Salt intake. \200 Lack of exercise. \200 Environmental stress. \200 Smoking. \200 Cholesterol. Is there target organ damage? 2 Think Brain, Eyes, Heart, Arteries, Kidneys. \200 Stroke, TIA, cognitive decline. \200 Fundi: hypertensive retinopathy. Grades 1 and 2 (silver wir ing and AV nipping) are common. Grades 3 and 4 (hemorrhage, exudates, papilloedema) carry a signi \201 cantly increased risk of stroke, CV disease, and CCF and require urgent treatment ( b p. 522). LVH, IHD, cardiomegaly, CCF. \200 Peripheral vascular disease: look for bruits \200\224 carotid, femoral, renal. \200 Renal impairment, proteinuria, microscopic haematuria. \200 Sexual dysfunction. CLINICAL ASSESSMENT 463 Investigations Routine \200 Urinalysis (? protein blood). \200 SCr, eGFR, U&E, Ca 2+ . \200 Blood glucose \200\224 preferably fasting. \200 Lipid pro \201 le \200\224 preferably fasti ng. \200 ECG for LVH ( i LV strain l higher risk) and/or evidence of IHD. For selected patients \200 Echocardiogram. \200 Urine protein evaluation: uACR or uPCR (if dipstick proteinuria). \200 Hb and Hct (polycythaemia). \200 Bicarbonate (hypokalae mic alkalosis?). \200 Thyroid function. \200 Ferritin (haemochromatosis). \200 ESR an d CRP. \200 Uric acid ( i in metabolic syndrome). \200 Plasma renin and aldosterone. \200 Plasma and urine metanephrines. \200 24h urinary sodium. \200 BP in lower limbs: hypertensive aged <40; older patient ? PVD. \200 Research investigations: vascular USS, p ulse wave velocity, assessment of endothelial function. Major cardiovascular risk factors \200 Hypertension. \200 Smoking. \200 Obesity (BMI \211 30). \200 Physical inactivity. \200 Dyslipidaemia. \200 Diabetes mellitus. \200 Albuminuria or GFR < 60mL/min. \200 Age ( \231\202 > 55 years, \231\200 > 65 year s). \200 Family history of premature CV disease ( \231\202 < 55 years, \231\200 < 65 ye ars). CHAPTER 6 Hypertension 464 Classi \201 cation and treatment thresholds There are many different classi \201 cations and guidelines, but all use similar BP targets (themselves based on evidence regarding CV o utcomes). The most important are those provided by: \200 The British Hypertension Society (BHS) and National Institute for Health and Care Excellence (NICE) \200\224a collaborative UK guideline. The European Society of Hypertension-European Society of Cardiology (ESH-ESC). The Joint National Committee (JNC) (USA). \200 Kidney Disease Improving Global Outcomes ( KDIGO) (i BP in the context of renal disease). All draw on the results of large randomized controlled trials and meta- analyzes to formula te their recommendations. BHS/NICE guideline The 2011 guidelines from BHS/NICE classify BP into stage 1, stage 2 and severe. They were also the \201 rst to use ambulatory (ABPM) and home BP (HBPM) measureme nts. NICE/BHS primary hypertension targets (2011) Clinic BP \200 < 140/90mmHg in people aged < 80 years. \200 < 150/90mmHg in people aged \211 80 years. Daytime average ABPM or average HBPM during waking hours \200 <135/85mmHg in people aged <80 years. \200 <145/85mmHg in people aged \211 80 years. Overview Offer lifestyle interventions and patient education to all. Stage 1 hypertension Clinic BP \211 140/90 mmHg and subsequent ABPM daytime average or HBP M average BP \211 135/85 mmHg. \200 Offer antihypertensive drug treatment if: TOD. \200 Established CV disease. \200 10-year CV risk \211 20% (see b p. 470). \200 DM. \200 CKD. Annual review. \200 If aged <40 years, consider more detailed evaluation of TOD and specialist referral (traditional CV risk calculators may underestimate lifetime risk). CLASSIFICATION AND TREATMENT THRESHOLDS 465 Stage 2 hypertension Clinic blood pressure \211 160/100 mmHg and subsequent ABPM daytime a verage or HBPM average BP is \211 150/95 mmHg. \200 Offer antihypertensive drug treatmen t. \200 Offer lifestyle interventions and patient education. \200 Annual review. Severe hypertension Clinic systolic BP \211 180mmHg or diastolic BP \211 110mmHg. \200 Start hypertensive drug immediately. Do not wait for ABPM. \200 Refer for specialist ca re immediately if: Accelerated hypertension (grade 3 or 4 hypertensive retinopathy). \200 Cardiovascular com plications. \200 New renal impairment, haemoproteinuria. \200 Suspected phaeochromocyto ma ( b p. 482). If hypertension is not diagnostic Clinic blood pressure is \211 140/90 mmHg or higher but subsequent ABPM or HBPM average BP is \211 135/85 mmHg. \200 Measure BP at least every 5 years. \200 If TOD, look for alternative causes. CBPM \211 160/100mmHg and ABPM/HBPM \211 150/95mmHg Stage 2 hypertension CBPM \211 140/90mmHg and ABPM/HBPM \211 135/85mmHg Stage 1 hypertension If target organ damage present or 10-year cardiovascular risk >20% Offer antihypertensive drug treatment Consider specialist referral If younger than 40 years Offer lifestyle interventions Offer patient education and interventions to support adherence to treatment Offer annual review of care to monitor blood pressure, provide support, and discuss lifesty le, symptoms, and medication Fig. 6.4 Care pathways in hypertension. Used with kind permission of NICE. CBPM, clinic BP monitoring; ABPM, ambulatory BP monitoring; HBPM, home BP monitoring. CHAPTER 6 Hypertension 466 The European Society of Hypertension-European Society of Cardiology (ESH-ESC) The latest ES H-ESC guideline was published in 2013. The full guideline is available at http://eurheartj. oxfordjournals.org/content/34/28/2159 The following summary is adapted with permission. Table 6.2 ESH-ESC classi \201 cation Category Systolic Diastolic Optimal < 120 and < 80 Normal < 130 and/or 80 \200\223 84 High normal 130 \200\223 139 and/or 85 \200\223 89 Grade 1 hypertension (mild) 140 \200\223 159 and/or 90 \200\223 99 Grade 2 hypertension (moderate) 160 \200\223 179 and/or 100 \200\223 109 \211 180 \211 110 Grade 3 hypertension (severe) and/or \211 140 Isolated systolic hypertension and/or < 90 Table 6.3 ESH-ESC de \201 nitions of i BP by of \201 ce and \200\230out of of \201 ce \200\231 BP measurement Category Systolic BP (mmHg) Diastolic BP (mmHg) \211 140 \211 90 Of \201 ce BP and/or Ambulatory BP \211 135 \211 85 Daytime (or awake) and/or \211 120 \211 70 Nighttime (or asleep) and/or \211 130 \211 80 24-h and/or \211 135 \211 85 Home BP and/or Summary of ESH-ESC treatment guidelines 2013 \200 Prompt initiation of drug treatment is recommended in individuals with grade 2 and 3 i BP with any level of CV risk, a few weeks a fter (or simultanous to) initiation of lifestyle changes. Lowering BP with drugs is recommended when total CV risk is high because of TOD, DM, CVD or CKD, even for grade 1 i BP Initiation of drug treatment should also be considered for grade 1 patients at low to moderate risk when BP is within this range at several repeated visits, o r elevated by ambulatory BP criteria - and remains within this range despite a reasonable p eriod of lifestyle measures. CLASSIFICATION AND TREATMENT THRESHOLDS 467 Drug treatment is recommended in elderly patients (age >60) when SBP is \211 160mmHg. Howe ver, treatment should also be considered in this group (esp. if age <80) if SBP is in the 1 50 \200\223160mmHg range, pro- vided that it is well tolerated. This recommendation in the elderly is an important change from previous ESH-ESC guidelines. A high normal BP should not be treated with antihypertensive drug therapy. Young individuals with isolated elevation of brachial SBP should not be treated (due to a lack of evidence), but should be followed closely with appropriate lif estyle recommendations. Treatment should target a BP <140/90mmHg. A lower target of <130/80mmHg in patients with CKD, diabetes or a CV disease is no longer recommended as it i s not adequately supported by evidence from RCTs. Table 6.4 Summary of ESH-ESC BP treatment goals (2013) Classa Levelb Recommendations A SBP goal <140 mmHg a) is recommended in patients at low-moderate CV risk; I B b) is recommended in patients with diabetes; I A c) should be considered in patients with previous IIa B stroke or TIA d) should be considered in patients with CHD; IIa B e) should be considered in patients or non-diabetic CKD. IIa B I A In elderly hypertensives less than 80 years old with SBP \211 160 mmHg there is solid evid ence to recommend reducing SBP to between 150 and 140 mmHg. IIb C In \201 t 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 tolera bility. In individuals older than 80 years old with initial SBP \211 160 mmHg, it is recommended t o reduce SBP to between 150 and 140 mmHg provided they are in good physical and mental cond ition. I B A DBP target of <90 mmHg is always recommended, except in patients with diabetes, in whom v alues <85 mmHg are recommended. It should nevertheless be considered that DBP values betwee n 80 and 85 mmHg are safe and well tolerated. I A aClass of recommendation; blevel of evidence CHAPTER 6 Hypertension 468 Joint National Committee (JNC) guideline The latest iteration of this in \202 uential guid eline has been delayed by an unprecedented degree of prerelease stakeholder scrutiny. Howev er, it is expected that JNC 8 (or JNC \200\230late \200\231 as it has been dubbed) may, li ke ESH-ESC, offer a more stringent interpretation of available data \200\224 retaining a go al of 140/90mmHg for the majority, but suggesting higher targets may be acceptable for many patients age >60 (and particularly age >80). JNC 8 may also echo ESH-ESC by offering a mor e circum- spect view of lower treatment targets (<130/80mmHg) in the presence of comorbidit ies such as diabetes and CKD. The current status is available at: M http://www.nhlbi.nih.gov/ guidelines/hypertension/jnc8/ KDIGO \200 Recommend a BP target <140/90mmHg for non-diabetic, non- proteinuric CKD patients Target <130/80mmHg if proteinuria (>30mg/24h) whether diabetic or not. Tailor treatment regimes for individual elderly patients by carefully considering age, co-morbidities and other therapies. Escalate treatment carefully under app ropriate supervision. X The J-curve phenomenon The question \200\230how low to go? \200\231 remains both valid a nd important. It is possible that there may be a threshold below which additional BP reduc- tion is no longer bene \201 cial. This could be explained by the maintenance of physiolog ical autoregulation within organ vascular beds, particularly in the presence of CV disease. The data supporting a \200\230lower the better \200\231 approach have come from meta-analy zes of multiple trials, rather than from studies speci \201 cally designed to scrutinize d ifferent target ranges. Indeed, some trials, such as ACCORD, have shown no consistent reduc tion in CV events, even when lower average SBPs are achieved. Furthermore, it has been in- ferred from some studies; e.g. ONTARGET that lower BP targets may actually be associated wi th additional coronary events. Many interpret the J-curve relationship to mean that BP reduction to lower levels, even if not harmful, is certainly less meaningful than a reduction to more moderate values. These issues are re \202 ected in the latest iterations of the guidelines discussed above, which have become more guarded in their recom- mendation of lower targets, even in high-ri sk groups. Overall, current evidence suggests that, even if escalating therapy to achieve the lowest p ossible BP is not clearly detrimental, neither is it clearly advantageous \200\224it may no t \210 be cost effective, with patients unnecessarily exposed to side effects that in \202 uence their overall compliance. CLASSIFICATION AND TREATMENT THRESHOLDS 469 Suggested indications for specialist referral \200 Urgent (inpatient) treatment needed: Accelerated hypertension (severe i BP, with grades III \200\223 IV retinopathy). Particularly severe hypertension (>220/120mmHg). \200 Hypertensive emergency (e.g. enceph alopathy, eclampsia, aortic dissection). Impending complications (e.g. LVF, TIA). Possible s hypertension. \200 Resistance to treatment ( \211 3 drugs). \200 Multiple drug intolerances. \200 Multiple drug contraindications. \200 Persistent non-adherence or non-compliance. \200 Other situations: Unusual blood pressure variability. \200 Possible white coat hypertension. \200 Hyperte nsion in pregnancy. CHAPTER 6 Hypertension 470 Cardiovascular risk assessment Formal assessment of CV risk is the starting point for treat ment decisions and discussions between clinicians and patients. The ultimate goal of the tr eatment of hypertension is prevention of CV disease. \200 The absolute risk of a CV event varies widely according to age, sex, severity of BP, and presence or absence of additional risk factors. The relative risk reduc tion of interventions is constant. Overprediction l overtreatment, underprediction l missed opportunity. Estimation of risk is straightforward in many patients; e.g. those with established CV dise ase, diabetes, CKD or a signi \201 cantly elevated single risk factor. In these situations CV risk is high and aggressive intervention highly desirable. Many patients, however, do not belong to such high-risk groups and estimation of risk requires the use of risk-prediction models. Many computerized models have been developed. None are perfect. They aim to identify patien ts for intervention and calculate potential risk reduction. Many are based on Framingham data*. However, Framingham studied a Caucasian, middle class p opulation on no treatment (i.e. no aspirin, statins etc.) and is several decades old. See w ww. framinghamheartstudy.org/risk Framingham-based scoring tends to overestimate CV risk in low and medium risk groups and underestimate CV risk in renal disease, diabetes, certain ethnic groups, those with LVH and those with FH of premature CHD. It has \210 been suggested th at the risk score should be adjusted by a factor of x 1.5 if there is one relative with pre mature CVD and by x 1.4 if the individual is a male of South Asian origin. \200 Many mode ls refer to 10-year risk of CV mortality. High risk refers to 10-year CV mortality of \211 20%. The Systematic Coronary Risk Evaluation (SCORE) model has been developed from large European cohort studies. It allows calibration for several different c ountries and is recommended by ESH-ESC. An inter- active version of SCORE is available thro ugh www.heartscore.org. \200 ASSIGN (www.assign-score.com) is based on Scottish data and takes FH and social deprivation into account. There is a move toward estimations of lifetime rather than 10-year risk. For example, the QRISK lifetime risk calculator identi \201 es younger patients with high lifetime risk (de \201 ned as >50%) who would not be identi \201 ed using 10-year r isk estimates. (www.qrisk.org). The prediction of lifetime risk is recommended by the Joint British Societies (see http://www.jbs3risk.com). Risk calculators may not be appropriate when individuals are at higher CV risk because of u nderlying medical conditions/treatments (e.g. HIV, autoimmune disease). Clinical judgment is important when making decisions in certain circumstances (e.g. obesity, taking statins, already on BP treatment, recently stopped smok ing). The Framingham Heart Study: a cohort of over 5,000 men and women, aged 30 \200\22362, from Framingham, Massachusetts, followed up from 1971 to assess the determinants of CV disease. CARDIOVASCULAR RISK ASSESSMENT 471 When you don \200\231t need a risk calculator: Assume the following groups of people are at high risk (10-year CVD risk \211 20%), rathe r than use risk calculators: \200 Pre-existing CVD. \200 DM. \200 CKD. \200 Familia l hypercholesterolaemia. CHAPTER 6 Hypertension 472 Lifestyle measures Lifestyle changes can d BP, reduce drug requirements, and improve CV ris k (see Table 6.5). The effects are synergistic. Clear advice, including culturally appropri ate written and audiovisual material, should be provided to all patients as well as to thos e with a high normal (pre-hypertensive) BP or positive family history.