explaining the bene \201 ts and potential side effects of drug treatment. Although marked interindividual variation in drug responses re \202 ects the heterogeneity of the pathogenesis of i BP, pro \201 ling patients, accor ding to their hypertensive phenotype with a view to individualizing drug therapy, has prove d dif \201 cult (exceptions: the elderly and ethnic groups). Drug withdrawal might be possible if other lifestyle interventions are undertaken and prove successful. The patient may bene \201 t from joining local or national forums (e.g. M http://www.bpassoc.org.uk ). Once BP is adequately controlled, provide at least an annual review for monitoring. The major drug groups are equally well tolerated. They are prescribed in 7 equal amounts in primary care: \200 Thiazide diuretics ( b p. 498). \200 ACE-I and ARBs ( b p. 508 \200\223511). \200 Calcium channel blockers (CCBs) ( b p. 506). \200 B -blockers ( b p. 502). In the UK, B -blockers have been \200\230 downgraded \200\231 and are not recommended as \201 rst-line therapy. However, it largely depends on which guideline you follow. \200 A -blockers are not recommended a s \201 rst line ( b p. 504). \200 X The optimal cardiovascular outcome is most consiste ntly linked with the level of BP control, rather than the class of drug used to achieve it. In general, the lower the BP, the better. Patients will be accruing bene \201 t, even if they do not achieve target BP. There are now generic versions of key medications, which has reduced the cost of choosing many drugs. It is helpful to consider compelling indications and compelling contraindications (see Table 6.8). There are also other less de \201 nite pros and cons th at will be assigned different importance by different prescribers. Timing of therapy may be important. If more than one agent is used, then having at least on e dose at bedtime may improve circadian BP, CV outcomes, and daytime BP control (this has b een demonstrated for both non-CKD and CKD populations in recent RCTs). DRUG MANAGEMENT OF HYPERTENSION 485 Aspirin and statins Consider prescribing other drugs that modify CV risk. \200 Aspirin 75 mg od: p prevention in hypertensives aged >50 and 10-year CV risk > 20% and BP <150/90mmHg, with no contraindication. s prevention of CV disease. Statin therapy: p prevention in hypertensives with 10-year CV risk > 20%. \200 s prevention in all with o vert CV disease, irrespective of baseline total cholesterol or LDL. Targets: d total choles terol by 25% or LDL cholesterol by 30%, or achieve a total cholesterol of < 4.0mmol/L or LD L cholesterol of < 2.0mmol/L (whichever is the greatest reduction). CHAPTER 6 Hypertension 486 r a l u c s a v o n e r r a l u c s a v o n e r e c n e n i t n o c n d n a k c o b s n o i t a c i d n i a r t n o c t r a e h y l b i s s o p / a m h t s A l d e h s i l s g u r d t r a e h g n , k c o b , , b a t s e y c n a n g e r P y c n a n g e r P i l l e p m o C i l d e s a e s i d d e s a e s i d y r a n i r U , D P O C e v i s n e t r e p y h i t n a e r u f t u o G t r a e H s i e r e h t l i a f \200\223 . l o n i r u p o n e h w e c v d a t r a e h s e t e b a d c c D V P C V P l l a , n o i s n e t o p y h i i h t i b , t n e m b , t n e m ) , h t i D V P c , e r u w n o i t a n b m o c D H C h t i f t s i l a c e p s o s e s s a l c w n o i t a n b m o C e d a k c o b - a t e b i r i a p m r i a p m i w n o i t u a C l i a f l a r u t s o P d n a t p e c x e ( l a e r u i i i t r a e H l a n e R l a n e R r o a m e h t , n n o i s i v r e p u s l i a f i j \200\223 d e s u . e s a e s i d l a n e r . e s a e s i d . c i t e b a d e s a e s i d e r u y l l a e d . n o i s i v r e p u s e c n a r e o t n l i a f r a l u c s a v o n e r e s o l c c n o r h c r o i i i , s g u r d t r a e h , t u o g r a l u c s a v l a n e r f I I l s n o i t u a c , n o i t u a c e p y t n e s r o w y a m f o y r o t s i h e v i s n e t r e p y h i t n a , c i r u n e t o r p i t s i l a c e p s e s a e s i d , I l a r e h p i r e p b , e s a e s i d M h t i s n o i t a c i d n c e r u i t s o p h t i i w n o i t a c o s s a w d e s u d n a l i a f l a n e r a r e d n u h t i n o i t c n u f s y d V L s r e k c o b - a t e b a n g n a l a n e r t r a e h , i , y h t a p o r h p e n w e p o e p e r u D V P , s n o i t a c d n a r t n o c i c i r u n e t o r p e b i e s a e s i d l l i a f e l b i s s o P l r e h t o c n o r h C y l n o d u o h s , ; , e s a e s i d i n o i s n e t r e p y h y l r e d E f o e s u a c e b i t r a e H n i r a l u c s a v o n e r I l i f M l o , r e v e w o H P B i l o r t n o c o t I t u b M e s a e s i d n o i s n e t r e p y h c i t e b a d c n o i t n e v e r p e k o r t s t s o p c i l e r u I I o t s y s I M . e r u e p y t h t i l i a f , s n o i t a c d n t s o p r a l u c s a v i y h p o r t r e p y h , n o i t c n u f s y d V L y r a s s e c e n l i a f w s t n e i t a p s d e t a l o s i l a n e r I , e c n a r e o t n e p y t , n t r a e h s n o i t a c i d n e r u , s t n e i t a p i e k o r t s e r u c n o r h c , l a r e h p i r e p l i a f y h t a p o r h p e n i i , D H C d e h s i l , e b a t s l i a f H S I e b l l n t r a e h i i c i t a t s o r p s e m t r a e h s d e s u e b i s s o p ; t n a r e o t n i - E C A i e s a e s i d n l ) . n o i s s i i r o t i b h n t a e r t o t i , , y h t a p o r h p e n g n e r u i t e m o s l a c \201 e n e b , H S I H S I n s e m n o i t n e v e r p i i i l l e p m o C , a n g n a l H V L s B R A d n a l i a f i b a t s e m r e p c i t e b a d i y r a n o m u p , , i t e m o s y l r e d E y l r e d E a n g n A n g n e B d e s u i t r a e H y a m d n a E C A i h t i i , I . e b y p a r e h t o n o m r o h t i M i l l w s c i t e r u d y l g n i s a e r c n l e r a y a m w d e s U g n s r o t i b h n . t n e m e v i t c u r t s b o c n o r h c i l l s B R A d n a ) e n d i r y p o r d y h d ( s B R A r o s r o t i b h n i e p m o C i e k e k r i a p m i . s e n ) g n i t i i i E C A h t i i l - e d i z a h t / e d i z a h T i l - e d i z a h t / e d i z a h T e r a s a i l e d u g s r o t i b h n i d e s u s r e k c o b - a h p A m s r o t i b h n s r e k c o b - a t e B g u r d f l a n e r s r e k c o b - a t e B i i i l - e t a r ( 8 6 i i w n o i t u a C . S H B m o r F ( n e h w F H i i i t n a c \201 n g i s i s c i t e r u d l l o s s a l C e l b a T i i l , D P O C E C A E C A i s B C C s B C C s B R A E C A i i i l i d b e c a f DRUG MANAGEMENT OF HYPERTENSION 487 CHAPTER 6 Hypertension 488 Guidelines for drug treatment Algorithms Guidelines have become increasingly didactic, as p revious less speci \201 c rec- ommendations generally proved ineffective. The British Hypertensive Society and NICE Two key UK advisory bodies published updated guid elines in 2011 on the treatment of hypertension (see Fig. 6.6). In the 2006 guidelines, B - blockers were downgraded in response to evidence suggesting they may be less effective at d major CV events (particularly stroke) than other drug classes and that they have a higher diabetes risk than ACE-I or CCBs (particularly in patients also taking a thiazide diuretic ( b p. 502)). In this recent update, there has been a change in the priority of medications in people >55 years, with CCB as the \201 rst-line choice, based on event reduction and cost effectiveness. Thiazide-like diuretics (e.g. indapamide) are suggested in those with h eart failure or very elderly who are intolerant of a CCB. B -blockers can still be used as possible \201 rst-line therapy in \231\200 of child- bearing potential and patients with evidence of i sympathetic drive. Renin pro \201 ling demonstrates that younger people (<55 years) and Caucasians have highe r renin levels, re \202 ecting an active RAS, relative to elderly and black patients. Sinc e ACE-I and ARBs act through RAS sup- pression, they are recommended as initial therapy in younger Caucasian patients. Recommendations (see algorithm in Fig. 6.6) \200 Step 1: People aged <55: initial therapy with an ACE-I/low-cost ARB. \200 People aged >55: initia l therapy with a CCB. \200 Black patients (any age): CCB (does not include mixed race, subcontinental Indian, or Chinese patients). Step 2: Add ACE-I (or low-cost ARB) to CCB (or vise versa). Step 3: Before considering step 3 treatment, ensure step 2 treatment is at optimal, or best tolerated, dose. Compelling indications/contraindications should be taken into account ( b p. 486). Recommendations in other guidelines The ESH-ESC guideline advocates the initiation of a dru g combination in high-risk patients or in those with a signi \201 cantly elevated presenti ng BP. It is thought that JNC 8 will take a similar view. In these circumstances, combined therapy should offer a greater potential for achieving target BP reduction and with fewer s ide effects than when maximizing the dose of a single agent (see Fig. 6.7). GUIDELINES FOR DRUG TREATMENT 489 Aged <55 or black patients of any age Aged <55 Step 1 C1 A A + C1 Step 2 Step 3 A + C + D Resistant hypertension Step 4 A + C + D + consider further diuretic2,3 or alpha blocker or beta blocker4 Consider specialist advice A \200\223 ACE inhibitor or low-cost angiotensin II receptor blocker (ARB) C \200\223 Cal cium channel blocker (CCB) D \200\223 Thiazide-like diuretic Fig. 6.6 2011 BHS/NICE recommendations for the drug treatment of hypertension. Used with ki nd permission of NICE. 1 A CCB is preferred, but consider a thiazide-like diuretic, if not tolerated, oedema, evidence/high risk of heart failure. 2 Consider a low dose of spironolac tone or higher doses of a thiazide-like diuretic. 3 At the time of publication (August 2011 ), spironolactone did not have a UK marketing authorization for this indication. Informed c onsent should be obtained and documented. 4 Consider an A - or B -blocker if further diuret ic therapy is not tolerated or is contraindicated or ineffective. Choose betweem Marked BP elevation High/very high CV risk Mild BP elevation Low/moderate CV risk Single agent Two \200\223drug combination Switch to different agent Previous agent at full dose Previous combination at full dose Add a third drug Full dose monotherapy Two drug combination at full doses Switch to different two \200\223drug combination Three drug combination at full doses BP = blood pressure; CV = cardiovascular. Fig. 6.7 Monotherapy vs. drug combination strategies to achieve target BP. Moving from a le ss intensive to a more intensive therapeutic strategy should be done whenever BP target is not achieved. Reproduced from 2013 ESH/ESC Guidelines for the management of arterial hypert ension, Eur. Heart. Jour . 34: 28, 2159 \200\2232219 (2013), with permission of Oxford Univ ersity Press. CHAPTER 6 Hypertension 490 BP treatment: special situations Hypertension in black patients The prevalence of i BP and related complications, such as CHD, stroke and renal disease, is higher in African American s than other ethnic groups. This holds true in the UK, with mortality data for England and Wales showing mortality 3.5 x the national average. British Asians have a mortal- ity rate 1.5 x the national average. There is evidence of differential BP-lowering ef \201 cacy of particular drugs within ethn ic groups, although the variability is greater within the groups than between them. The rec ommendation of CCB in this group is based on greater treatment effects, compared to ACE-I/A RB. If not tolerated, diuretic therapy is useful, as there is a higher prevalence of salt-s ensitive i BP and increased salt and water retention likely to contribute to the increased i BP. Black patients, in general, have a lower renin, and so agents (ACE-I, ARB, and B -blo ckers) that suppress renin production may not be as effective, especially when used as mono therapy. The International Society of Hypertension in black people (M http://www.ishib.org ) has made recommendations for treatment and favor the initiation of combi- nation therapy in individuals with more signi \201 cant hypertension. Hypertension in the elderly CHD and stroke remain the major killers in those aged >65, with BP the commonest treatable risk factor. SBP increases with age. DBP increases to age 60, plateaus, and then falls. This leads to an age-related increase in pulse pressure and isolated SBP. BP variability also increases 6 more measurements are desirable prior to treatment. Using a relatively conservative de \201 nition of i BP ( \211 160/95mmHg), it is estimated that > 15% of the 12 million people aged > 60 in the UK are hypertensive ( > 70% aged \211 80 ). i BP in the elderly is 6 a major public health issue. Clinical trials have shown that older people bene \201 t just as much, if not more, from i ntervention as younger patients. A study of those \211 80 years (Hypertension in the Very Elderly (HYVET), with target BP 150/80mmHg, showed overwhelming CV bene \201 ts from trea tment. 1 This needs to be balanced against the risk of orthostatic hypertension ( l falls l fractures). You may need to titrate treatment to the standing BP value, and DBP should not be reduced to <65mmHg. Low renin hypertension is the norm, so begin treatment with a thiazide or CCB. For second l ine, ACE-I/ARBs are demonstrably more effective than B -blockers. Other lifestyle interventions still apply. Hypertension in diabetes mellitus (See b p. 612.) Hypertension in CKD (See b pp. 203 \200\2234.) Hypertension in pregnancy (See b p. 846.) BP TREATMENT: SPECIAL SITUATIONS 491 Oral contraceptives, HRT, and BP Oral contraceptives \200 The combined oral contraceptive (COC) modestly i BP in a minority of women ( 7 1%). Occasionally, elevations may be severe. The rise in BP may not b ecome apparent for several months, or even years, after COC introduction. The mechanism(s) of i BP remain uncertain, and it has proved dif \201 cult to identify women at particular risk. COC use is also associated with increased stroke and MI risk. BP should be measured prior to COC use and at least every 6 months thereafter. Progestogen-only pills have not been associated with i BP and are recommended for women with both COC-induced i BP and pre-existing i BP. In those women wishing to remain on the COC, antihypertensive medication should be given early considerati on. \200 For older women (aged > 35) with higher CV risk (e.g. smokers), non-hormonal forms of contraception are preferable. Hormone replacement therapy (HRT) \200 HRT use is not associated with i BP, and its use i s not contraindicated in pre-existing hypertensives. Several large randomized trials have established that the CV protection afforded by HRT has been overplayed previously and should not be used as the mot ivation for their prescription. CHAPTER 6 Hypertension 492 Clinical trials in hypertension The bene \201 ts of BP lowering are supported by one of th e most authorita- tive evidence bases in clinical medicine. The foundation of this evidence base is the prospective randomized clinical trial. Trial designs \200 Duration rarely > 5 years. \200 Endpoints: All-cause mortality. \200 Cause speci \201 c morbidity and mortality (usually CHD str oke; more recently, CCF). The \200\230 composite p endpoint \200\231 has emerged (i.e. a combination of events) bec ause trials seldom have suf \201 cient power to examine speci \201 c outcomes. Early trials compared active therapy with placebo, often among patients with severe i BP. Consequently, they had high power and could be conducted on a re latively small scale. Such trials became unethical, as the bene \201 ts of BP lowering bec ame apparent. Modern \200\230 head-to-head \200\231 trials tend to assess whether drug classes offer ad vantages over others (drug companies are desperate to demonstrate bene \201 ts \200\230 b eyond BP lowering \200\231 ). BP differences between treatment arms now tend to be minimal, 6 d study power and necessitating i patient numbers. Contemporary treatment objectives also in \202 uence trial design \200\224 most patients now require multiple drugs to achieve target. The majority of patients at high CV risk will be receiving concomitant treatment with aspir in a statin, further diminishing study power. Trials are hugely expensive. \200 The data from clinical trials are often pooled for meta -analysis. This can provide increased power to examine drug-speci \201 c effects. See Table 6.9 for recent major trials. X Controversies \200 Do speci \201 c classes of drugs offer bene \201 ts for CV disease prevention beyond the expected bene \201 ts of BP lowering? \200 There are marked drug-speci \201 c differences in their effect on CV structure and function as well as metabolic endpoints. The relevance of these effects on longer-term outcomes remains unknown. Could certain classes of drugs be potentially harmful with regard to speci \201 c outcomes? With regard to study design, can treatment be solely measured in terms of CV events or is t he real aim to prevent the evolution of a destructive disease process? Clinical trials rarely run for more than 5 years, while life expectancy in middle-aged hypertensives is 20 \200\223 30 years. CLINICAL TRIALS IN HYPERTENSION 493 Meta-analysis of BP-lowering trials: the BPLTTC The Blood Pressure Lowering Treatment Trial ists Collaborative (BPLTTC) was formed over 10 years ago and is an international alliance o f the principal investigators of the largest trials of antihy- pertensive regimens. The pro ject is based at the George Institute for International Health, a department of the Univers ity of Sydney (M http://www.georgeinstitute.org/projects/blood-pressure-lowering- treatment -trialists-collaboration-bplttc ). Its objective is to address questions concerning safety and outcome with speci \201 c drug classes. To achieve this, data from recent trials are pooled and subjected to meta-analysi s ( 6 providing the necessary statis- tical power to examine drug-speci \201 c effects). Analysis includes differential drug effects in diabetes, between the sexes, and for the risk of major CV effects. Analysis published in 2003, * incorporated data from 29 randomized controlled trials involv ing 7 160,000 patients, with a mean duration of follow-up of 2.0 \200\223 8.0 years ( > 70 ,000 patient years). The mean age was 65 years (52% \231\202 , 48% \231\200 ). Conclusion s \200 Treatment with any of the commonly used regimens d the total risk of major CV events. Larger reductions in BP produce larger reductions in risk. \200 ACE-I and diuretics B -blockers are more effective at preventing heart failure than regimens based on CCBs. Other differences in regimens \200\230 beyond BP lowering \200\231 are less certain (including for stroke). Turubull F et al . (2003) Lancet 362 : 1527 \200\223 1535. CHAPTER 6 Hypertension 494 Table 6.9 Major trials in hypertension Study acronym Full name Purpose To determine whether lowering BP below recommended CV goals or particular agents slowed the progression of hypertensive renal disease (GFR 20 \200\223 65mL/min). Patients received r amipril or amlodipine, with both compared to metoprolol. AASK African American Study of Kidney Disease and Hypertension JAMA (2002); 288: 2421 \200\223 31 The largest double-blind, randomized trial of hypertensive patients (n = 42,418). Hypothesi s: fatal CHD and non-fatal MI would be lower in patients randomized to \200\230 new \200 \231 drugs (ACE-I and CCBs), as compared to those taking a thiazide. ALLHAT The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial JAMA (2002) ; 288: 2981 \200\223 97 To compare the effects on CHD of a B -blocker 9 diuretic ( \200\230 old-fashioned \200 \231 ) vs a CCB 9 ACE-I ( \200\230 modern \200\231 ) in patients with i BP. A second arm ( Lancet (2003); 361 : 1149 \200\223 58) compared atorvastatin with placebo for i lipids i n hypertensive patients. ASCOT The Anglo-Scandinavian Outcomes Trial Lancet (2005); 366 : 895 \200\223 906 HOPE Heart Outcomes Prevention Evaluation Study NEJM (2000); 342: 145 \200\223 53 To compare ramipril to placebo for the prevention of CV events in patients with evidence of atherosclerotic CV disease taking standard therapy ( 7 50% non-hypertensive). To assess the relationship of major CV events with three target DBPs ( \211 90, \211 85 , or \211 80mmHg). Also whether low dose aspirin, in addition to d BP therapy, d CV event s. HOT Hypertension Optimal Treatment Study Lancet (1988); 351 : 1755 \200\223 62 CLINICAL TRIALS IN HYPERTENSION 495 Table 6.9 (Continued) Result Comment Ramipril was superior in d rate of decline. The amlodipine arm was stopped early because of worse outcomes. Showed (surprisingly) that the level of BP attained did not affect the rate of decline of r enal function. General conclusion: thiazide diuretics are unsurpassed in preventing the major complication s of i BP. They are also well tolerated and inexpensive. They became the initial drug of ch oice in many guidelines. Criticisms: (i) designed in an era of monotherapy, (ii) many concl usions drawn on the basis of s endpoints, (iii) randomization deprived some patients with C CF of their diuretic, (iv) old- fashioned treatments were used for step-up (e.g. clonidine, reserpine). A doxazosin arm was stopped early (median 3.3 years \200\231 follow-up) after interim data suggested an i risk of combined CHD events. Main \201 nding was that thiazides, CCBs, an d ACE-I all provide similar protection from CHD. Thiazides appeared superior to CCBs and AC E-Is in preventing some adverse CV outcomes. CCBs not associated with excess CV deaths \200\224 a concern in previous studies. Unique in its focus on combination therapy. Good press for CCBs after a lot of (unjusti \201 ed) bad press. Reignited concerns regarding new-onset DM with diuretics + B -blocker. Led to early review of guidelines. Stopped early (median follow-up 5.4 years) because of superior results in the CCB/ACE-I arm for several s endpoints, including all-cause mortality and new-onset DM ( p endpoints were non-fatal MI and fatal CHD). Substudy with atorvastatin treatment resulted in a signi \201 cant d in the incidence of stroke. Provided considerable impetus to the \200\230 beyond BP lowering \200\231 hypothesis. The re were important BP differences between the groups that probably accounted for the results (and led cynics to dub it the \200\230 HYPE \200\231 trial). Ramipril decreased the combined relative risk of MI, stroke, or CV death by 22%. De \201 ned a new optimal BP target (DBP 83mmHg), Further reductions did not d CV events ( i.e. did not support the \200\230 J curve \200\231 hypothesis). Achieved BPs were 144/85, 141/83, and 140/81. The lowest incidence of CV events occurred at DBP 83mmHg. The bene \201 t of progressive BP reduction was most marked in patients with DM. Aspirin caused a further signi \201 cant d in CV events (due entirely to a d in MIs). (Continued) CHAPTER 6 Hypertension 496 Table 6.9 (Continued) Study acronym Full name Purpose HYVET Hypertension in the Very Elderly Trial NEJM (2008); 358 : 1887 \200\223 98 To compare outcomes in 3,845 very elderly patients (aged \211 80) for placebo and a diure tic (indapamide) 9 ACE-I (perindopril). INSIGHT Intervention as a Goal in Hypertension Treatment Lancet (2000); 356 : 366 \200\223 72 To compare CV events in high-risk hypertensive patients treated with nifedipine or amilorid e + hydrochlorothiazide. To compare the long-term effects of losartan with atenolol on CV mortality and morbidity in hypertensive patients with LVH. LIFE Losartan Intervention for Endpoint Reduction in Hypertension Lancet (2002); 359 : 995 \200 \223 1003 To investigate if dual therapy with ACE-I and ARB would offer additional cardiovascular and renal protection. ONTARGET Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial NEJM (200 8); 358 : 1547 \200\223 59 PROGRESS Perindopril Protection against Recurrent Stroke Study Lancet (2001); 358 : 1033 \200\223 4 0 To investigate whether perindopril alone, or in combination with indapamide, in \202 uence d stroke recurrence ( 7 50% patients non-hypertensive). Patients aged 70 \200\223 84 were assigned to either an ACE-I, a dihydropyridine CCB, or a \200\230 conventional \200\231 therapy ( B -blocker 9 diuretic). To investigate whether antihypertensive treatment in elderly patients with isolated SBP could d CV events (primari ly stroke). Participants received placebo or nitrendipine (with enalapril and hydrochloroth iazide added, if needed). STOP-2 The Swedish Trial in Old Patients with Hypertension-2 Lancet (1999); 354 : 1751 \200\223 6 SYST-EUR Systolic Hypertension \200\224 Europe Lancet (1997); 354 : 757 \200\223 64 VALUE Valsartan Antihypertensive Long-term Use Evaluation Lancet (2004); 363 : 2022 \200\223 31 To investigate whether, for the same level of BP control, valsartan is more effective than amlodipine in d CV events. CLINICAL TRIALS IN HYPERTENSION 497 Table 6.9 (Continued) Result Comment Demonstrated effective treatment in age 80 years or older is bene \201 cial, extending the patient group in whom prevention should be considered. Stopped early because of superior results in treatment arm for overall mortality and stroke . Final results showed additional d in CV events as well as fatal and non-fatal heart failu re. Both regimens resulted in equivalent BP control and outcomes. The diuretic group needed signi \201 cantly more add-on antihypertensive medications. Less new-onset DM was seen in the CCB group. One interpretation: the bene \201 ts of losartan extend beyond its BP-lowering effects. An other: apparent bene \201 ts of losartan actually due to negative effects of atenolol. BP control was identical between the two groups. p events were fewer, the incidence of new- onset DM lower, and LVH regression greater for losartan than for the B -blocker. No differences in composite p outcome between ACE-I/ARB or combination but increased incide nce of ESRD and renal impairment with combination therapy Combination therapy was associated with more adverse events without increased bene \201 t. This changed practice with respect to dual therapy. Those on perindopril had a signi \201 cant d in recurrent stroke. Often cited as evidence for the \200\230 beyond BP lowering \200\231 hypothesis \200\231 for ACE-I, but the improved stroke outcome was probably driven by the more pronounced d in BP in the combined perindopril + diuretic arm. No difference in p endpoints among the three arms. ACE-I was associated with a lower risk o f MI and CCF than those treated with a CCB. Suggested newer and older drugs are generally equivalent. Stopped early because of a 42% d in stroke in the active arm. Cardiac events were also redu ced but not signi \201 cantly. Also suggested CCBs may have a protective role in vascular dementia. Good BP control in groups underscored the importance of achieving target BP, whatever the a gent(s) used. There were no differences between treatment groups in CV morbidity or mortality. CHAPTER 6 Hypertension 498 Diuretics 1 Introduction (see also b p. 792) Diuretics act by directly inhibiting the Na + transporters/channels mediat- ing renal Na + reabsorption. Ef \201 cacy depends on active secretion of the diuretic into the proximal nephron so that high concentrations are achieved at sites of action along the tubule. Renal insuf \201 ci ency impairs proximal secretion l relative diu- retic resistance. Higher doses may still be effective but risk i toxicity. The Na + and volume loss associated with diuretics is initially accompa- nied by the activa tion of vasoconstrictor mechanisms (including RAS). This is one of the reasons that diureti cs and ACE-I/ARBs are a good combina- tion (see Fig. 6.8). Thiazide-type diuretic Examples \200 Thiazides: bendro \202 umethiazide, hydrochlorothia zide. \200 Thiazide-like: chlortalidone, indapamide. Mechanism \200 Compete with both Na + and Cl \200\223 to block the Na + \200\223 Cl \200\223 co-transporter in the DCT (normally responsible for 5 \200\223 7% of \201 ltered Na + reabsorption). i Na + delivery to distal nephron l i Na + /K + exchange and, indirectly, i H + excretion. Hypokalaemic metabolic alkalosis often results. \200 Blocking the Na + \200\223 Cl \200\223 co-transporter l i Ca 2+ reabsorption. There are a number of potentia l mechanisms for this, but the relative contributions are unknown. It is most likely that c hronic volume depletion leads to more proximal reabsorption. Thiazides 6 have a role in pre vention of renal stone disease and exert a protective effect in osteoporosis. Thiazide-like agents differ in several of their actions, including duration of action, channel-blocking activity, and inhibitory in \202 uence on carbonic anhydrase. Role \200 Effective, good evidence base, and inexpensive. \200 Introduced in 1957 and s till the \201 rst line in several guidelines. \200 Evidence for bendro \202 umethiazid e comes from studies with higher doses than those used in clinical practice now. For this r eason, thiazide-like agents are now considered \201 rst choice over thiazides. \200 i p lasma half-life and sustained renal actions make them preferable to loop diuretics as antih ypertensives (except in special situations, b p. 500). Problems \200 Hypokalaemia (dose-dependent). \200 Impaired glucose tolerance (especiall y when used with a B -blocker). \200 Small i in LDL cholesterol and triglycerides. \200 Small i serum urate. DIURETICS 1 499 Erectile dysfunction. \200 Ef \201 cacy d in those taking NSAIDs. \200 Avoid if histor y of gout \200 Avoid if taking lithium ( i risk of lithium toxicity). Thiazide diuretics Angiotensin-receptor blocker Beta-blockers Other Antihypertensives Calcium antagonists ACE-inhibitors ACE = angiotensin-converting enzyme. Fig. 6.8 Possible combinations of different classes of antihypertensive agents. The preferr ed combinations in hypertensive populations are represented as thick lines. The frames indi cate agents proven to be bene \201 cial in interventional studies. Reproduced from 2013 ES H/ESC Guidelines for the management of arterial hyper- tension, Eur. Heart. Jour. 34: 28, ( 2159 \200\2232219 (2013), with permission of Oxford University Press. CHAPTER 6 Hypertension 500 Diuretics 2 Loop diuretics Examples Furosemide, bumetanide. Mechanism \200 Block the type 2 Na + K + 2Cl \200\223 (NKCC2) co-transporter in the thic k ascending limb of the loop of Henle (usually responsible for 15 \200\223 20% of \201 lte red Na + reabsorption). Tubuloglomerular feedback would normally act to compensate by a d in GFR, but this is depen dent on an identical ( 6 inhibited) co-transporter in the macula densa. Like thiazide diuretics, may cause hypokalaemic metabolic alkalosis. \200 Initial Na + an d volume loss may be compensated for by Na + retention during the latter part of the dosing interval, with amelioration of BP-lowering ef \201 ca cy. So, more frequent dosing (at least twice daily) is necessary when used for treatment of hypertension. Role More potent natriuretics than thiazide-type diuretics but less effective BP-lowering a gents. Their place in the management of i BP is limited to patients with CCF (with volume o verload), renal impairment (with volume overload), and other oedematous states (e.g. cirrho sis). Sequential nephron blockade This is a strategy to overcome diuretic resistance in oedematou s states that involves combination therapy with loop and thiazide (or thiazide-like) diuret ics. Potassium-sparing diuretics Examples Amiloride, triamterene. Mechanism \200 Block the epithelial Na + channel (ENaC) expressed in the late DCT and collecting duct. \200 ENaC plays a central role in the control of urinary Na + reabsorption, ECF volume homeostasis, and BP regulation. Several hormones, including aldosterone, vasopressin, angiotensin II, insulin, and endothelin, regulate ENaC activity. K + absorption is tightly coupled with ENaC Na + absorption. Drugs blocking ENaC 6 cause K + retention. Also has Mg 2+ -sparing effects. Role Not \201 rst-line. \200 Useful adjuncts to limit d K + and d Mg 2+ with other diur etics. d K + may actually i BP and is associated with insulin resistance, DM, arrhythmias, and sudden death. DIURETICS 2 501 Amiloride may be used to prevent d K + and i BP associated with excess glucocorticoids or mineralocorticoids ( b p. 477) and in Liddle \200\231 s syndrome (caused by activating mutation(s) in ENaC) ( b p. 801). Can be useful in black patients where ENaC may play a more prominent role. Can be useful in patients with suspected hyperaldosteronism who are avoiding spironolactone/eplerenone before ARR testing. Problems 1 Hyperkalaemia! Cautions: renal impairment (especially in DM), com- bination with B -blockers, ACE-I/ARB, or spironolactone. The incidence of i K + when amiloride is co-pre scribed with a thiazide or loop diuretic is very low. Mineralocorticoid antagonists Increasingly recommended as the fourth-line agent for resista nt hyper- tension. Why is this? \200 Aldosterone activates mineralocorticoid receptors in the heart, vasculature, and brain. Adverse consequences of activation include endothelial dysfunction, myocardial \201 brosis, myocyte hypertrophy, vascular injury, and centrally mediated ele vations in BP. RAS activation is associated with worse outcomes in patients with CCF and i BP. Although ACE-I and ARBs d aldosterone production, levels return toward normal with chronic use. Plasma aldosterone levels correlate with LVH in hypertensive patients. \200 Patients with p hyperaldosteronism have worse CV outcomes. \200 Pharmacological blockade of mineraloco rticoid receptors d LVH and microalbuminuria in hypertensive patients. Experience in severe CCF is positive, with a d in mortality (RALES study). Spironolactone has long been used in the treatment of conditions associated with s hyperaldosteronism and volume expansion, such as cirrhotic ascites. Spironolactone and eplerenone are the mineralocorticoid receptor antagonists in clinical us e. \200 Spironolactone is recommended as \201 rst line on ef \201 cacy and cost ground s. Highly effective. It can be used in combination with thiazide-like diuretics. Not actual ly licensed for use in hypertension in the UK (license withdrawn in the 1980s due to concer ns re malignancy in rodents. This has not been borne out in humans, but patients should be informed of the off-license use). Eplerenone is a selective mineralocorticoid receptor with 20 x af \201 nity for mineraloco rticoid receptor but just 75% potency of spironolactone. However, less af \201 nity for an drogen and progesterone receptors l fewer SE. Adverse effects: gynaecomastia (common), GI upset, impotence, i K + ( 1 caution with ACE-I and ARB, especially if renal impairment). CHAPTER 6 Hypertension 502 B -blockers Competitive inhibitors of catecholamines at B -adrenergic receptors. Many are a vailable, with marked interdrug differences in pharmacodynamic and pharmacokinetic properti es. In general, these characteristics in \202 uence clearance and side effect pro \201 le , rather than ef \201 cacy. Examples See Table 6.10. Mechanism Remains a matter of debate. Potentially: \200 d cardiac output. \200 d renin release. \200 d plasma volume. \200 d vasomotor tone. \200 d peripheral vascular resi stance. \200 Improved vascular compliance. \200 Resetting of baroreceptor levels. \200 Effects on prejunctional B receptors: d noradrenaline release. \200 d pressor response to catecholamines with exercise and stress. \200 Direct CNS effect. Role Downgraded in BHS/NICE in the UK and not \201 rst choice in JNC-7 although still use ful if concomitant angina, post-MI ( d mortality risk), arrhythmias, or hyperdynamic circul ation. Consider in younger people and if resist- ant i BP. Carvedilol, metoprolol, and biso prolol have been shown to d morbidity and mortality in patients with stable CCF. Labetalol is useful in pregnancy ( b p. 849) and for parenteral treatment ( b p. 522). Problems \200 Avoid in marked bradycardia, AV node disease. \200 Avoid abrupt withdrawa l, as rebound tachycardia can cause myocardial ischaemia in susceptible individuals. X Many patients with obstructive airways disease have compelling indications for B -blocker therapy (IHD/CCF/arrhythmias). B 1 selective agents (atenolol or metoprolol) appear to be safe and may actually reduce exacerbations and mortality. Can cause lethargy, impaired concentration and memory, vivid dreams, hallucinations, depression (CNS effects may be more prominent with lipid-soluble agents), d eterioration in peripheral vascular disease (nebivolol has some peripheral vasodilating pro perties and may well be tolerated in patients with claudication), and Raynaud \200\231 s s ymptoms. Metabolic effects: d HDL cholesterol and i triglycerides. \200 i likelihood of new-onset DM, particularly wh en combined with a thiazide (combination leads to 7 1 new case of DM for every 250 patients treated/year.) Avoid this combination if high risk: strong FH of T2DM, impaired glucose to lerance (FPG \211 6.5mmol/L), clinically obese (BMI >30), or of South Asian or Afro-Carib bean origin. B-BLOCKERS 503 Worsen glycaemic control and hypoglycaemic awareness in T1DM (worse with non-selective agents). Combined with diltiazem or verapamil, may cause slowing of SA node negative inotropic effect. Table 6.10 Examples of B -blockers B 1 - selectivity a A -blocking activity d Intrinsic sympath- omimetic activity b Membrane- stabilizing activity c Major route of elimination e Acebutolol 1 + + + Renal Atenolol 1 ++ Renal Bisoprolol ++ Both Carvedilol ++ + Hepatic Celiprolol + + Both Labetalol ++ Hepatic Metoprolol 1 ++ Hepatic Nadolol 1 Renal Nebivolol + + Renal Oxprenolol 1 Hepatic Pindolol 1 ++ + Both Propranolol ++ Hepatic Sotalol 2 \200 + Renal Timolol 1 Hepatic