recent guidelines for the management of arterial hypertension (part ii)

Recent Guidelines for the Management of Arterial Hypertension

(Part II)

Christos G. SavopoulosAssistant Professor of Internal Medicine

1st Propedeutic Department of Internal MedicineDepartment of Vascular Diseases and Hypertension

AHEPA University HospitalAristotle University of Thessaloniki

Thessaloniki, Central Macedonia, Greece

Initiation of antihypertensive treatment (differentiations)

JNC-7 2003

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

Hypertension. 2003;42:1206–52 J Hypertens 2007;25(9):1751-62

ESH/ESC 2007ESH/ESC 2007

5 major classes: Thiazide diuretics ACE inhibitors (ACEi) ARBs β-blockers Calcium antagonists (CA)

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


The choice of a specific drug or drug combination and the avoidance of others should take into account:

1. Previous favorable or unfavorable experience of the individual patient with the given class of agents

2. The effect of drugs on CV risk factors in relation to the CV risk profile of the individual patient

3. Presence of subclinical organ damage, clinical CV disease, renal disease or diabetes, which may be more favorably treated by certain drugs than others

4. 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

5. The cost of drugs, although cost considerations should never predominate over efficacy, tolerability and protection of the individual patient


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

Antihypertensive treatment Preferred drugs

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 treatmentPreferred drugs

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

Compelling and possible contraindications to use of antihypertensive drugs

Compelling Possible

Thiazide diuretics Gout Metabolic syndromeGlucose intolerancePregnancy

Beta-blockers AsthmaAV block (grade 2 or 3)

Peripheral artery diseaseMetabolic syndromeGlucose intoleranceAthletes and physically active patientsChronic obstructive pulmonary disease

Calcium antagonists(Dihydropyridines)

TachyarrhythmiasHeart failure

Compelling and possible contraindications to use of antihypertensive drugs

Compelling PossibleCalcium antagonists(verapamil/diltiazem)

AV block (grade 2 or 3)Heart failure

ACE inhibitors PregnancyAngioneurotic oedemaHyperkalaemiaBilateral renal artery stenosis

Angiotensin receptor antagonists (AT1 blockers)

PregnancyHyperkalaemiaBilateral renal artery stenosis

Diuretics(antialdosterone)

Renal failureHyperkalaemia

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


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


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

Advantages & Necessity of Combination therapy

Bakris GL et al. Am J Kidney Dis. 2000;36:646-661

ΜBP < 92 SBP (mm Hg)AASK Blacks

DBP < 80HOT DM

MBP < 92MDRD CRD

DBP < 75ABCD DM

DBP < 85UKPDS DM

DBP/ΜBP (mm Hg)

Clinical trialsnumber of antihypertensive drugs

0 1 2 3 4

INVEST 136CONVINCE 137 ALLHAT 138 IDNT 138 RENAAL 141 UKPDS 144 ABCD 132 MDRD 132 HOT 138 AASK 128

Number of antihypertensive drugs

1 2 30 4

Monotherapy vs. combination therapyAlgorithm of alternative therapeutic

procedures

Mild BP elevation

Low/moderate CV risk

Conventional BP target

Marked BP elevation

High/very high CV risk

Lower BP target

Choose between

Single agent 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

Two-to three-drug combination at full dose

Full dosemonotherapy

If goal BP not achieved

Two-three drug combination at full doses

Two-drug combination at low dose

Thiazide diuretics

Calcium antagonists

β-blockers *

α-blockers

ACE inhibitors

Angiotensin receptor antogonists

Possible combinations between classes of antihypertensive drugs (differentiations)

* Intermittent red line, since β-blockers, especially in combination with thiazide diuretics, should

not be used in metabolic syndrome, DM or risk of developing DM

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.

Specific therapeutic approach in special groups

Antihypertensive 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

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 of the 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


Antihypertensive 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

M

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


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

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


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

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 relationship with 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


Antihypertensive 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)


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

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 hypertension such as isolated office hypertension (white-coat) or failure to use large cuffs on large arms or pseudohypertension (elderly)

Causes of resistant hypertension Poor adherence to 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

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)

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-eclampsia or eclampsia (cerebral oedema and seizures in pregnancy)

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


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%)

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

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

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

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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recent guidelines for the management of arterial hypertension (part ii)

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