Comments on Reappraisal of European Guidelines on Hypertension Management:

a European Society of Hypertension Task Force Document V. Gerc Clinic for heart disease and rheumatisam

Introduction

• In the 2 years since the publication of the 2007 guidelines for the management of arterial hypertension of the European Society of Hypertension and ESC , research on hypertension has actively been pursued and the results of new important studies have been published.

Introduction

• The aim of this document of the ESH is to address a number of studies on hypertension published in the last 2 years in order to assess their contribution to our expanding knowledge of hypertension.

Failure to reach JNC 7 blood pressure goals in hypertension subgroups Patients not at goal % % Patient subgroup Uncomplicated Black Elderly Diabetic Goal systolic/diastolic BP, mm Hg Systolic BP Diastolic BP < 140/90 < 140/90 < 140/90 < 130/85 64 62 78 81 26 37 9 24

Subclinical OD in Total CV Risk Quantification (I)

• In HT assessment of total CV risk it is important to optimize decision about treatment initiation / intensity / goals • Quantification of total CV risk must include search for subclinical OD, which is common and has independent prognostic significance • In HTs the presence of subclinical OD usually brings CV risk into the high range • Subclinical OD may not be sufficient to bring NTs into the high risk category, although this may occur with multiple OD and the metabolic syndrome

Subclinical OD in Total CV Risk Quantification (II)

• Several measures of renal, cardiac and vascular damage can be considered for total CV risk quantification • Because of their simplicity, wide availability and limited cost measures based on urinary protein excretion (including microalbuminuria), eGFR (MDRD formula), and EKG are suitable for routine use

Subclinical OD in Total CV Risk Quantification (III)

• Cardiac and vascular ultrasounds are more and more easily available in Europe, and their use in the evaluation of the hypertensive patient can be encouraged • Subclinical OD should be assessed both at screening and during treatment because a number of treatment-induced changes in OD relate to CV and renal outcomes, thereby offering information on whether the selected treatment is protecting patients

BP Goal(s)

• Sufficient evidence to recommend that SBP be lowered to < 140/90 in both low-moderate and high risk HTs • Evidence missing in the elderly (benefits of lowering SBP to < 140 mmHg never tested in randomized trials)

BP Goal(s)

• Considering additional (weaker) evidence it may be prudent to recommend lowering BP within the 130-139/80-85 mmHg range in all HTs, and possibly close to lower values in this range • More critical evidence from specific randomized trials desirable

Treatment Initiation at High Normal BP (130-139/85-89 mmHg) • If no diabetes / previous CV events no trial evidence of treatment benefits (except of delayed new HT) • No prospective trial evidence also in diabetes treatment recommended if organ damage (particularly renal) is present • Trial evidence in patients with previous CV events controversial - further trials to be completed before firm recommendation can be given

Initiation of Drug Treatment

• Prompt drug treatment in grade 2/3 HT • Reasonable to make use of drug treatment also in grade 1 HT, although no trial evidence in grade I hypertensives at mild / moderate risk

Initiation of Drug Treatment

• Recommendation to start drug treatment at BP ≥ 140/90 mmHg in the elderly as well although evidence mainly based on “Post-hoc” event data - Improvement of organ damage - Delayed treatment leads to irreversible organ damage / greater residual risk

Choice of Antihypertensive Drugs (I)

• Large scale meta-analyses do not confirm the contention that major antihypertensive drug classes differ significantly for their ability to reduce BP • There is also no undisputable evidence that major drug classes differ in their ability to protect against overall CV risk or cause-specific CV events, e.g. stroke and myocardial infarction

Choice of Antihypertensive Drugs (I)

• The 2007 ESH/ESC guidelines conclusion that D / ACEI / CA / ARB / BB can all be considered suitable for initiation / maintenance of antihypertensive treatment can thus be confirmed

Choice of Antihypertensive Drugs (II)

• Each drug class has contraindications as well favourable effects in specific clinical settings. The choice of drugs should be made according to this evidence • The traditional ranking of drugs into first / second / third and subsequent choice, with an average patient as reference, has now little scientific and practical justification and should be avoided

2007 ESH/ESC Hypertension Guidelines First Choice Drug Treatment

• Diuretics * • ACE-inhibitors • Calcium antagonists • Angiotensin receptor antagonists • Beta-blockers* *

not to be initially preferred in patients at high risk of developing diabetes

ESH/ESC Guidelines 2007: Recommended initial antihypertensive drug

Thiazide diuretics β-blockers ARB

α- blockers

C CB ACEi

BP Reduction and CV Protection

• BP reduction

per se

plays a major role in CV and renal protection of hypertensive patients • The greater the number of available therapeutic options to lower BP the better

Combination Treatment

• New and old evidence strongly suggests combination treatment as the most effective strategy to control BP • Treatment strategies should be largely based on the addition of a drug from another class to the initially prescribed one whenever BP control is not achieved (unless the starting drug needs to be changed because of side effects or the absence of any BP reduction)

Fixed-dose (or Single Tablet) Combinations

• Guidelines have long favoured the use of two-drug combinations in a single tablet (improvement in compliance which is low in hypertension) • Whenever possible, use of single tablet combinations should be preferred, because simplification of treatment carries advantages for compliance to treatment

Combination Therapy (I)

• Evidence has continued to show that in the

vast majority of HTs effective BP control can only be achieved by combination of at least two antihypertensive drugs

• Addition of a drug from another class to the initially prescribed one should thus be regarded as a recommendable treatment strategy, unless the initial drug needs to be withdrawn because of the appearance of side effects or the absence of any BP lowering effect

Combination Therapy (II)

• The two drug combination may offer advantages also for treatment initiation, particularly in high CV risk patients in whom early BP control may be desirable • Whenever possible, use of fixed dose (or single pill) combinations should be preferred, because simplification of treatment carries advantages for compliance to treatment

Choice of Combinations

• Despite trial evidence of outcome reduction, the BB / diuretic combination favours development of diabetes and should thus be avoided, unless required for other reasons, in predisposed subjects

Choice of Combinations

• Several drug combinations are suitable for clinical use • Trial evidence of outcome reduction has been obtained particularly for the combination of - Diuretic + ACEI - Diuretic + ARB - Diuretic + CA - ACEI + CA • The ARB + CA combination also appears to be rational and effective • These combinations should thus be recommended for priority use

Choice of Combinations

• Use of an ACEI / ARB combination presents a dubious potentiation of benefits with a consistent increase of serious side effects • Specific benefits in nephropathic patients with proteinuria (because of a superior antiproteinuric effect) expect confirmation in event based trials

ON

going

T

elmisartan

A

lone and in combination with

R

amipril

G

lobal

E

ndpoint

T

rial

The telmisartan trial in cardiovascular protection

Sponsored by Boehringer Ingelheim

Indication and evidence for combining ACEI and ARB Indication Hypertension Systolic heart failure Post myocardial infarction Nephroprotection (diabetics) Yes Nephroprotection (non diabetics) Da Indication for dual RAS inhibition Not standard, possibly in LVH, microalbuminuria, DM Yes, when symptoms persist despite diuretic, beta blocker, and ACEI No

Preferred Combinations

• The ARB/CA combination has several potential advantages (effective BP reduction / high rate of BP control / highly favourable tolerability profile / protection against organ damage). It has never been tested / widely used in outcome trials, except for RENAAL (together with D)

Preferred Combinations (II)

• Successful outcome trials have also used the BB/D combination, which however more easily induces new onset diabetes in predisposed subjects • New evidence warns against the ARB/ACEI combination (dubious additional benefits but more frequent serious side effects) at least in high risk patients

Combinations Tested or Widely Used in Outcome (CV-renal events) Trials

ACEI / D PROGRESS ADVANCE HYVET ACEI / CA Syst-Eur Syst-China INVEST ASCOT HOT ACCOMPLISH CA / BB HOT (2 nd used) ARB / D LIFE SCOPE RENAAL CA / D FEVER ELSA VALUE ARB / CA RENAAL (with D as well)

Three Drug Combinations

• In no less than 15-20% of HTs BP control cannot be achieved by a two drug combination • When three drugs are required, the most rational combination appears to be a RAS blocker, a calcium antagonist and a diuretic at effective doses

Why ARB +Amlodipine ?

No ARB+CCB ARB+diuretic ACEI+diuretic ACEI+diuretic ACEI+CCB ACEI+CCB ACEI+CCB BB+diuretic Valsartan + HCTZ Losartan + HCTZ Irbesartan + HCTZ Candesartan + HCTZ Telmisartan + HCTZ Olmesartan + HCTZ Eprosartan + HCTZ Benazepril + HCTZ Lisinopril + HCTZ Benazepril + amlodipine Enalapril + felodipine Trandolapril + verapamil Atenolol + chlorthalidone Co-Diovan Hyzaar Avalide Atacand Plus Micardis Plus Benicar HCT Teveten HCT Lotensin HCT Prinzide Lotrel Lexxel Tarka Tenoretic

Conceptual Rationale for ARB +Ca antag.

Leveraging synergy of counter-regulation   Amlodipine  Arteriodilation  Peripheral edema Effective in low-renin patients Reduces cardiac ischemia BP Valsartan  RAS blockade  CHF and renal benefits   Valsartan  Venodilation  Attenuates peripheral edema Effective in high-renin patients No effect on cardiac ischemia

Synergistic BP reduction Complementary clinical benefits

Amlodipine  RAS activation  No renal or CHF benefits

ACEI / CA Combination

• Tested or widely used combination therapy in Syst-Eur / Syst-China / HOT / ASCOT / INVEST / ACCOMPLISH • Greater CV protection than placebo in Syst-Eur / Syst-China • Equal (INVEST) or greater (ASCOT) CV protection than D/BB • Greater CV protection than ACEI/D in ACCOMPLISH

Avoiding Cardiovascular Events through COMbination Therapy in Patients LIving with Systolic Hypertension

Kenneth Jamerson 1 , George L. Bakris 2 , Bjorn Dahlof 3 , Bertram Pitt 1 , Eric J. Velazquez 4 , and Michael A. Weber 5 for the ACCOMPLISH Investigators University of Michigan Health System, Ann Arbor, MI 1 ; University of Chicago-Pritzker School of Medicine, Chicago, IL 2 ; Sahlgrenska University Hospital, Gothenburg, Sweden 3 ; Duke University School of Medicine, Durham, NC 4 ; SUNY Downstate Medical College, Brooklyn, NY 5

ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy

90 80 70 60 50 40 30 20 10 78.5

37.2

ACEI / HCTZ N=5733 P<0.001 at 30 months follow-up

Control defined as <140/90 mmHg

81.7

37.9

CCB / ACEI N=5713 Baseline Control Rates

Kaplan Meier for Primary Endpoint

ACEI / HCTZ 20% Risk Reduction

650

CCB / ACEI

526

p = 0 .0002

Time to 1 st CV morbidity/mortality (days) HR (95% CI): 0.80 (0.72, 0.90)

INTERIM RESULTS Mar 08

Primary Endpoint and Components

Composite CV mortality/morbidity Cardiovascular mortality Non-fatal MI Non-fatal stroke Hospitalization for unstable angina Coronary revascularization procedure Resuscitated sudden death Risk Ratio (95%) 0.80 (0.72

–0.90) 0.81 (0.62-1.06) 0.81 (0.63-1.05) 0.87 (0.67-1.13) 0.74 (0.49-1.11) 0.85 (0.74-0.99) 1.75 (0.73-4.17) 0.5

Favors CCB / ACEI 1.0

Favors ACEI / HCTZ 2.0

ARB / CA Combination

• The ARB/CA combination presents with several advantages - Effective BP reduction - High rate of BP control - Highly favourable tolerance profile (better than the ACEI / CA combination) - Protection against organ damage • However, it has never been tested / widely used in outcome trials • An exception is RENAAL in which nephroprotection by ARB was seen on a background of common treatment with CA (but also D)

Combinations of More than Two Drugs

•

No less than 15%-20% of the patients need more than two antihypertensive drugs

to achieve an effective BP reduction •

The combination of a RAS blocker, a CA and a thiazide may be a rational three drug combination

• Other drugs such as  -blockers or an  -blocker may be included in this multiple approach, depending on the clinical circumstances

Triple combination

• Triple combination angiotensin receptor blocker Olmesartan, calcium channel blocker Amlodipine and diuretic Hydrochlorothiazide, has greater reductions in both systolic and diastolic blood pressure compared with the three dual therapies

Drug Combinations in Hypertension: Recommendations of ASH Preferred 2-drug combinations ACE inhibitor/diuretic* ARB/diuretic* Acceptable 2-drug combinations Unacceptable 2 drug combinations Beta-blocker/diuretic* ACE inhibitor/ARB CCB/diuretic ACE inhibitor/beta blocker ARB/beta blocker ACE inhibitor/CCB* Renin inhibitor/diuretic ARB/CCB* Thiazide diuretic/potassium sparing diuretic CCB (nonhydropyridine)/ beta blocker Centrally acting agent/beta blocker

Threshold / Target BP for Treatment in DM

• Antihypertensive treatment to be always initiated when BP ≥ 140/90 mmHg • Limited trial support for treatment initiation at high normal BP / to be recommended in the presence of organ damage (e.g. microalbuminuria) • The < 130/80 BP goal not supported by trial evidence / very difficult to achieve • Realistic to pursue a sizeable BP reduction without indicating a goal which is unproven

Antihypertensive Drugs in Diabetics

• • • Meta-analyses of available trials show that in diabetes all major antihypertensive drug classes protect against CV complications, probably because of the protective effect of BP lowering per se. They can thus all be considered for treatment

In diabetes combination treatment is commonly needed to effectively lower BP A renin angiotensin receptor blocker should always be included

because of the evidence of its superior protective effect against initiation or progression of nephropathy

Microvascular Complications

• Microvascular complications of diabetes in different organs are differently affected by treatment • Antihypertensive treatment exerts a major protective effect against renal complications, while evidence of a similar effect on eye and neural complications is less consistent

Blood Glucose Control in Diabetics

• In hypertensive diabetic patients tight blood glucose control (HbA 1C to 6.5%) is beneficial, particularly in microvascular complications • Recent evidence suggests that combining effective blood glucose and BP control increases protection, particularly of the kidney • Tight blood glucose control should not be pursued abruptly and patients should be monitored closely because of the increased risk of severe hypoglycaemic episodes

Antihypertensive Treatment in the Elderly (I)

• In the elderly antihypertensive treatment is highly beneficial (large meta-analyses) • In patients aged ≥ 65 the proportional benefit is no less than in younger patients • Data (large meta-analyses) do not support the claim that antihypertensive drug classes significantly differ in their ability to lower BP / exert CV in younger and in elderly patients protection both

Antihypertensive Treatment in the Elderly (II)

• The choice of the drugs to employ should thus not be guided by age • Thiazide diuretics / ACEIs / CA / ARBs / BBs can be considered for initiation / maintenance of treatment also in the elderly

Antihypertensive Treatment in the Elderly (III)

• In the elderly outcome trials have only addressed patients with an entry SBP > 160 mmHg • In no trial in which a benefit was achieved SBP averaged < 140 mmHg

Antihypertensive Treatment in the Elderly (IV)

• Common sense considerations suggest that also in the elderly drug treatment can be initiated when SBP > 140 mmHg with the goal of going below this value • Treatment should be conducted with particular attention to adverse responses, potentially more frequent in the elderly

Treatment in Patients Aged ≥ 80 Years

• Evidence is now available from an outcome trial (HYVET) that antihypertensive treatment has benefits also in patients aged 80 years or more • BP lowering drugs should thus be continued or initiated when patients turn 80, starting with monotherapy and adding a second drug if needed

Antiplatelet Therapy (I)

• A large meta-analysis of available trials confirms that antiplatelet treatment is highly beneficial in secondary CV prevention • The same meta-analysis shows that in primary prevention trials on subjects with an overall low risk antiplatelet treatment is associated with only a very tiny excess of benefit over harm

Antiplatelet Therapy (II)

• Although the benefit of antiplatelet treatment in diabetes (with or without hypertension) remains to be established, there is some evidence that low-dose aspirin may be beneficial (primary prevention) in HTs with a serum creatinine > 1.3 mg/dl or an eGFR < 45 ml/min .

1.73m

2 • Thus low-dose aspirin should be prescribed in HT without a previous CV event if there is a reduced renal function or a high risk • Careful attention should be given to the possibility of bleeding, particularly gastrointestinal

Lipid Lowering Treatment

• The recommendation to consider statin therapy in high risk HTs (ASCOT) confirmed • Association of statin with CA possibly more protective than with BB • Data from Jupiter trial support that statins can be beneficial also in subjects with moderate CV risk (15% in 10 ys) and elevated CRP

Erectile Dysfunction (ED)

• ED is prevalent in HT and predicts future CV events • Screening and treatment of ED useful • After initiation treatment with PDE-5-inhibitors patients are more likely to take antihypertensive medications and BP control is improved • Older antihypertensive drugs (diuretics / BBs / central agents) exert negative effects whereas newer drugs have either neutral (CA / ACEIs) or beneficial (ARBs) effects

Atrial Fibrillation (AF) - Primary Prevention

• In 2007 ESH / ESC guidelines recommendation to preferentially use ARBs / ACEIs • Evidence mainly from post-hoc analyses

Atrial Fibrillation (AF) - Primary Prevention

• Also plausible pathophysiological explanation, i.e. effectiveness of RAS blocker on LVH regression and relationship of LVH regression with AF • No consistent support from recent trials - TRANSCEND - PROFESS - I-Preserve

Atrial Fibrillation

• In a meta-analysis on almost 12.000 patients with systolic HF BBs were found to reduce (-27%) AF • In patients with an AF history and systolic HF BBs are a specific indication

Protection against Recurrent AF

• In 2007 ESH/ESC guidelines preferential use of ARBs / ACEIs recommended, with stress on small number of patients / need for new studies • No support from two new studies - CAPRAF - GISSI-AF (85% HTs) • Support from recent meta-analysis by Schmieder et al (?)

The Issue of the Polypill

• The rationale upon which the polypill has been developed is not the reasonable one of assembling several drugs to facilitate treatment of high risk patients requiring multiple therapies • The rationale is that, by containing all types of agents capable of reducing CV risk, the polypill may reduce CV risk by more than 80% in all individuals, and should be given to all individuals of 55 years and older

Criticism of the Polypill

• Aspirin in low risk individuals has only small CV benefits counterbalanced by excess bleeding • Antihypertensive agents lower BP only very moderately in NTs • Statins are generally well tolerated but sometimes accompanied by serious adverse events • The extent of the benefit of antihypertensive drugs / statins in individuals without any risk factor is unproven • The concept of treating “ CV risk ” as an entity without targeting and monitoring the individual risk factors appears unsound

New Antihypertensive Drugs

• Vasopressin antagonists • Neutral endopeptidase inhibitors • AT 2 receptor agonists • Endothelin receptor antagonists • Renin inhibitors

Resistant hypertension: endothelin antagonist darusentan

Efficacy of darusentan

New Antihypertensive Drugs

• Vasopressin antagonists • Neutral endopeptidase inhibitors • AT 2 receptor agonists • Endothelin receptor antagonists

• Renin inhibitors

Aliskiren

• Aliskiren is an orally active, direct inhibitor of renin wich simultaneously reduces angiotensin I, angiotensin II and plasma renin activity. Aliskiren introduces a new concept into the management of hypertension.

Binding of renin inhibitors to the active site of renin

Mechanism of action of direct renin inhibitors

Renin Inhibition Reduces PRA and Other Components of RAS ACEI ARB Diuretic Renin inhibitor Ang I

↑ ↑ ↑

↓ Ang II

↓ ↑ ↑

↓ Renin

↑ ↑ ↑

↑ PRA

↑ ↑ ↑

↓

Nussberger et al. J Hypertens 2002; Azizi et al. JASN 2004

Safety and Tolerability

Patients with AE (%) (n=131) Any AE Placebo 32.1

D/C due to AE Serious AE 2.3

0.8

Headache Diarrhea Dizziness Fatigue Back pain 5.3

1.5

3.8

3.1

– 150 mg (n=127) 26.8

3.9

– Aliskiren 300 mg (n=36.) 36.2

3.1

– 600 mg (n=130) 33.1

2.3

– 2.4

Most Frequent AEs ( ≥2%) 6.2

4.6

1.6

1.6

0.8

1.6

0.8

3.1

3.8

2.3

6.9

2.3

1.5

1.5

Irbesartan 150 mg (n=134) 36.6

2.2

0.7

3.0

1.1

3.7

1.5

4.5

Gradman AH et al. Circulation 2005;111:1012

Antihypertensive efficacy of the renin inhibitor aliskiren

New Trials Needed

• Should antihypertensive drug treatment be prescribed in grade 1 HT (BP 140-159 / 90-99 mmHg) when total CV risk is low-moderate?

• Should antihypertensive drugs be prescribed in the elderly with grade 1 HT with the goal to go < 140/90 mmHg?

New Trials Needed

• Should antihypertensive drugs be started when BP is in the high normal range in diabetics / patients with CVD history with the goal to go <130/80 mmHg?

• What are the lowest safe BP values to achieve in different clinical conditions?

• Are lifestyle measures known to reduce BP capable of reducing morbidity / mortality in HT?