Recent Guidelines for the Management of Arterial Hypertension (Part II)

1. Recent Guidelines for the Management of Arterial Hypertension(Part II) Christos G. Savopoulos Assistant Professor of Internal Medicine 1st Propedeutic Department of Internal Medicine Department of Vascular Diseases and Hypertension AHEPA University Hospital Aristotle University of Thessaloniki Thessaloniki, Central Macedonia, Greece

2. Initiation of antihypertensive treatment (differentiations) JNC-7 2003 ESH/ESC 2007 Thiazide diuretics can be used intially As first choice therapeutic agents, one drug from the following categories can be used: ACE inhibitors Angiotensin receptor blockers (ARBs) β-blockers Calcium antagonists 5 major classes: Thiazide diuretics ACE inhibitors (ACEi) ARBs β-blockers Calcium antagonists (CA) Hypertension. 2003;42:1206–52 J Hypertens 2007;25(9):1751-62

3. Choice of antihypertensive drugs • The main benefits of antihypertensive therapy are due to lowering of BP per se • All five major classes of antihypertensive are suitable for the initiation and maintenance of therapy, alone or in combination • As in many patients more than one drug is needed, emphasis on identification of the first class of drugs to be used is often futile • Nevertheless, there are many conditions for which there is evidence in favor of some drugs vs. others, either as initial treatment or as part of a combination therapy

4. Choice of antihypertensive drugs The choice of a specific drug or drug combination and the avoidance of others should take into account: • Previous favorable or unfavorable experience of the individual patient with the given class of agents • The effect of drugs on CV risk factors in relation to the CV risk profile of the individual patient • Presence of subclinical organ damage, clinical CV disease, renal disease or diabetes, which may be more favorably treated by certain drugs than others • Presence of other disease, which can be affected by the used antihypertensive drug, as well as the possibility of interaction between antihypertensive drug and drug used for the other disease • The cost of drugs, although cost considerations should never predominate over efficacy, tolerability and protection of the individual patient

5. Choice of antihypertensive drugs • Attention must be given to side effects of drugs, because they are the most important cause of non-compliance. Drugs are not equal in terms of adverse effects particularly in individual patients • BP lowering effect should last 24 hours. This can and should be checked by office or home BP measurements at trough or by ambulatory BP monitoring • Drugs with 24 hours action after an once-a-day administration should be preferred, because a simple treatment schedule favors compliance

6. Subclinical organ damages LVH Asymptomatic atherosclerosis Microalbuminuria Renal dysfunction Condition Isolated systolic hypertension (in the elderly) Metabolic syndrome Diabetes mellitus Pregnancy Blacks Preferred drugs ACEi, CA, ARBs CA, ACEi ACEi, ARBs ACEi, ARBs Diuretics, CA ACEi, ARBs, CA ACEi, ARBs CA, methyldopa, β-blockers Diuretics, CA Antihypertensive treatment Preferred drugs

7. Clinical event Previous stroke Previous MI Heart failure Angina pectoris Atrial fibrillation recurrent continuous Renal failure/proteinuria Peripheral artery disease Preferred drugs Any BP lowering agent β-blocker, ACEi, ARBs Diuretics, β-blocker, ACEi, ARBs, antialdosterone agent β-blocker, CA ACEi, ARBs β-blocker, non-dihydropiridine CA ACEi, ARBs, loop diuretics CA Antihypertensive treatmentPreferred drugs

8. Compelling and possible contraindications to use of antihypertensive drugs

9. Compelling and possible contraindications to use of antihypertensive drugs

10. Monotherapy vs. combination therapy Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number of hypertensives Monotherapy • Reduces BP ~ 4-8% (e.g. 160/95 151/89 mmHg) • Adequate BP control only in 50% of hypertensives Combination therapy (with two drugs) • Reduces BP ~ 8-15% (e.g. 160/95 143/85 mmHg) • Adequate BP control in ~ 70% of hypertensives ISH/WHO Hypertension Guidelines 1999 J Hypertension 1999; 17 (2): 151-163

11. Monotherapy vs. combination therapy • Use of more than one agent is necessary to achieve target BP in the majority of patients • Monotherapy could be the initial treatment for a mild BP elevation, classified as grade 1, with a low or moderate total CV risk • A combination of two drugs at low doses should be preferred as first step treatment when initial BP is classified as grade 2 or 3 or total CV risk is high or very high

12. Monotherapy vs. combination therapy • Fixed combination of two drugs can simplify treatment schedule and favor compliance • In several patients (~ 30%) BP control is not achieved by two drugs and a combination of three or more drugs is required • In uncomplicated hypertensives and in the elderly, antihypertensive therapy should normally be initiated gradually. In high risk hypertensives, goal BP should be achieved more promptly

13. Clinical trials DBP/ΜBP(mm Hg) UKPDSDM DBP <85 ABCDDM DBP <75 MDRDCRD MBP <92 HOTDM DBP <80 AASKBlacks ΜBP <92 SBP(mm Hg) Advantages & Necessity of Combination therapy Number of antihypertensive drugs 0 1 2 3 4 INVEST 136 CONVINCE 137 ALLHAT 138 IDNT 138 RENAAL 141 UKPDS 144 ABCD 132 MDRD 132 HOT 138 AASK 128 Bakris GL et al. Am J Kidney Dis. 2000;36:646-661

14. Marked BP elevation High/very high CV risk Lower BP target Mild BP elevation Low/moderate CV risk Conventional BP target Monotherapy vs. combination therapyAlgorithm of alternative therapeutic procedures Choose between Single agent at low dose Two-drug combination at low dose If goal BP not achieved Previous agent at full dose Switch to different agent at low dose Previous combination at full dose Add a third drug at low dose If goal BP not achieved Two-to three-drug combination at full dose Full dose monotherapy Two-three drug combination at full doses

15. Thiazide diuretics β-blockers* α-blockers Calcium antagonists ACE inhibitors Possible combinations between classes of antihypertensive drugs (differentiations) Red lines represent the preferred combinations in the general hypertensive population. Yellow background indicate classes of agents proven to be beneficial (CVE reduction) in controlled intervention trials. Angiotensin receptor antogonists *Intermittent red line, sinceβ-blockers, especially in combination with thiazide diuretics, should not be used in metabolic syndrome, DM or risk of developingDM

16. Specific therapeutic approach in special groupsAntihypertensive treatment in the elderly • Randomized trials in elderly have shown that a marked reduction in CV morbidity and mortality can be achieved with effective antihypertensive treatment • Drug treatment can be initiated with thiazide diuretics, Ca++ antagonists, ARBs, ACEi and β-blockers, in line with general guidelines. • Trials specifically addressing treatment of isolated systolic hypertension have shown more benefit of thiazide and calcium antagonists, but subanalysis of other trials also show efficacy of ARBs • Initial doses and subsequent dose titration should be more gradual, because of a greater chance of undesirable effects, especially in very old and frail subjects

17. Antihypertensive treatment in the elderly • BP goal is the same as in younger patients, < 140/90 mmHg or below, if tolerated, while many elderly patients need two or more drugs to achieve this • In subjects aged ≥80 yrs, evidence for benefits of antihypertensive treatment is as yet inconclusive, despite positive results of HYVET Study (2008). However, there is no reason for interrupting a successful and well tolerated therapy when a patient reaches 80 yrs or over • Because ofthe increased risk of postural hypotension, BP should always be measured also in the standing position • Drug treatment should be tailored to the risk factors, target organ damage and associated CV and non-CV conditions that are frequent in the elderly

18. M Specific therapeutic approach in special groupsAntihypertensive treatment in diabetics • Where applicable, intense non-pharmacological measures should be encouraged, with particular attention to weight loss and reduction of salt intake in type 2 diabetic patients • Goal BP should be lower <130/80 mmHg and so antihypertensive drug treatment may be started already when BP is in the high normal range • To lower BP, all effective and well tolerated drugs can be used. A combination of two or more drugs is frequently needed

19. Antihypertensive treatment in diabetics • Lowering BP exerts a protective effect on appearance and progression of renal damage. • Additional protection can be obtained by the use of a blocker of RAS (either ARB or ACEi). It should be a regular component of combination treatment and the one preferred when monotherapy is sufficient • Microalbuminuria should prompt the use of antihypertensive drug treatment also when initial BP is in the high normal range. Blockers of RAS have a pronounced antiproteinuric effect and their use should be preferred • Treatment strategies should consider an intervention against all CV risk factors, including hypolipidaemic therapy with statins • Because of the greater chance of postural hypotension, BP should also be measured in the standing position

20. Specific therapeutic approach in special groups Antihypertensive treatment in patients with renal dysfunction • Renal dysfunction and failure are associated with a very high risk of CV events • Protection against progression of renal dysfunction has two main requirements: a) strict BP control (<130/80 mmHg and even lower if proteinuria is >1 g/day); b) lowering proteinuria to values as near to normal • To achieve the BP goal, combination therapy of several antihypertensive agents (including loop diuretics) is usually required

21. Antihypertensive treatment in patients with renal dysfunction • To reduce proteinuria, an ARB, an ACEi or a combination of both are required • There is a controversial evidence as to whether blockage of the RAS has a specific beneficial role in preventing or retarding nephrosclerosis in non-diabetic non-proteinuric hypertensives (except perhaps in Afro-American individuals). However, inclusion of one of these agents in the combination therapy appears well founded • An integrated therapeutic intervention with antihypertensive, hypolipidaemic and antiplatelet therapy has to be frequently considered in patients with renal damage, because under these circumstances, CV risk is extremely high

22. Specific therapeutic approach in special groups Antihypertensive treatment in patients with cerebrovascular disease • In patients with a history of stroke or TIA, antihypertensive treatment markedly reduces the incidence of stroke recurrence and also lowers the associated high risk of cardiac events • Antihypertensive treatment is beneficial in hypertensive patients as well as in subjects with BP in the high normal range. So, BP goal should be <130/80 mmHg (PROGRESS Study) • Because evidence from trials suggests that the benefit largely depends on BP lowering per se, all available drugs and rational combinations can be used. • Trial data have been mostly obtained with ACEi and ARBs, in association with diuretic treatment, but more evidence is needed before their specific cerebrovascular protective properties are established

23. Antihypertensive treatment in patients with cerebrovascular disease • In acute stroke, there is at present no evidence that BP lowering to normal levels, has a beneficial or detrimental effect concerning penumbra perfusion. Until more evidence is obtained, antihypertensive treatment should cautiously start when post-stroke clinical conditions are stable (daily BP reduction < 15%) • In observational studies, cognitive decline and incidence of dementia have a positive relationshipwith BP values. There is some evidence that both can be somewhat delayed by antihypertensive treatment • Additional research in this area is necessary, because cognitive dysfunction is present in about 15% and dementia in 5% of subjects aged ≥65 years

24. Specific therapeutic approach in special groupsAntihypertensive treatment in patients with coronary heart disease and heart failure • In patients surviving MI, early administration of β-blockers, ACEi or ARBs reduces the incidence of recurrent MI and death • Due to specific protective properties of these drugs, but possibly also associated to a not abrupt BP reduction (DBP < 70 mmHg, undesirable) • In patients with chronic CHD, a beneficial effect has been demonstrated when initial BP is <140/90 mmHg and for achieved BP around 130/80 mmHg or less • Treatment of chronic ischemic heart disease and heart failure can make use of diuretics, β-blockers, ACEi, ARBs and antialdosterone drugs • CA such as dihydropyridines of 1st generation, should be avoided, because of undesirable tachycardia, unless needed to control BP or anginal symptoms (newer agents or non- dihydropyridines)

25. Specific therapeutic approach in special groups Antihypertensive treatment in patients with atrial fibrillation (AF) • Increased LV mass and LA enlargement are independent determinants of AF and require antihypertensive therapy • Strict BP control is required in patients under anticoagulant treatment to avoid intracerebral and extracerebral bleeding • Less new onset and recurrent AF has been reported in hypertensive patients treated with ARBs (LIFE Study) • In permanent AF, β-blockers and non-dihydropyridine CA (verapamil/diltiazem) help to control ventricular rate

26. Resistant hypertension Definition: BP ≥ 140/90 mmHg despite treatment with at least three drugs (including a diuretic) in adequate doses and after exclusion of spurious hypertensionsuch asisolated office hypertension(white-coat) orfailure to use large cuffs on large armsor pseudohypertension(elderly)

27. Causes of resistant hypertension • Poor adherenceto therapeutic plan • Failure to modify lifestyle: • Weight gain • Heavy alcohol intake • Obesity - Obstructive sleep apnea • Continued intake of drugs that raise blood pressure (liquorice, cocaine, glucocorticoids, non-steroid anti-inflammatory drugs, etc.) • Unsuspected secondary cause • Organ damage • Volume overload : • Inadequate diuretic therapy • Progressive renal insufficiency • High sodium intake • Hyperaldosteronism

28. Treatment of resistant hypertension • Adequate investigation of causes • Use of more than three drugs, adding an aldosterone antagonist (since in many cases an occult hyperaldosteronism might be present)

29. Hypertensive emergencies • Hypertensive encephalopathy • Hypertensive left ventricular failure • Hypertension with myocardial infarction • Hypertension with unstable angina • Hypertension and dissection of the aorta • Severe hypertension associated with subarachnoid haemorrhage or cerebrovascular accident • Phaeochromocytoma crisis • Recreational drugs effects (amphetamines, LSD, cocaine or ecstasy) • Perioperative hypertensive crisis • Pre-eclampsiaoreclampsia (cerebral oedema and seizures in pregnancy)

30. ESH/ESC 2007 Total cardiovascular risk • All patients should be classified not only in relation to the grades of hypertension but also in terms of total cardiovascular risk resulting from the coexistence of different risk-factors, organ damage and disease • Decisions on treatment strategies, as initiation of drug treatment, BP threshold and target for treatment, use of combination treatment, need of other non-antihypertensive drugs, all importantly depend on the initial level of risk

31. Total cardiovascular risk • Total risk is usually expressed as the absolute risk of having a cardiovascular event within 10 years. • There are several methods (e.g Framingham or PROCAM Score) by which total cardiovascular risk can be assessed. • Categorization of total risk as low, moderate, high and very high, added risk has the merit of simplicity and can therefore be recommended. The term “added risk” refers to the risk additional to the average one. • Patients with high and very high added risk, require use of Lipid Lowering Agents such a statin, Antiplatelet Therapy with aspirin and tight Glycaemic Control (glycated haemoglobin <7%)

32. Patient’s follow-up • Titration of BP control requires frequent visits in order to timely modify the treatment regimen in relation to BP changes and appearance of side effects • Once target BP has been obtained, the frequency of visits can be considerably reduced (usually every 3 months) • Patients at low risk or with grade 1 hypertension may be seen every 3 months and regular home BP measurements may further extend this interval. • Visits should be more frequent in high or very high risk patients. This is also the case in patients under non-pharmacological treatment alone, due to the variable antihypertensive response and the low compliance to this intervention

33. Patient’s follow-up • Follow-up visits should aim at maintaining control of all reversible risk factors as well as at checking the status of organ damage. • Because treatment-induced changes in left ventricular mass and carotid artery wall thickness are slow, there is no reason to perform these examinations at less than 1 year intervals • Treatment of hypertension should be continued for life, because in correctly diagnosed patients, cessation of treatment is usually followed by return to the hypertensive state. • Cautious downward titration of the existing treatment may be attempted in low risk patients after long-term BP control, particularly if non pharmacological treatment can be successfully implemented

34. How to improve compliance to treatment • Inform the patient on the risk of hypertension and the benefit of effective treatment • Provide clear written and oral instructions about treatment • Tailor the treatment regimen to patient’s lifestyle and needs • Simplify and reducing treatment plans, if possible • Involve patient’s partner or family in information on disease and treatment plans • Teach the use of self measurement of BP at home and of behavioral strategies • Sensitize to pay attention to side effects and be prepared to timely change drug doses or types if needed • Discuss with patient regarding adherence and his/her problems • Provide reliable support system and affordable prices

35. ESH/ESC 2007 Significance of guidelines • The ESH/ESC Guidelines have been prepared on the basis of the best available evidence (Evidence Based Medicine) • Health professionals are encouraged to take them fully into account when exercising their clinical judgment, but they do not override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients

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