1. 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

2. 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.

3. 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.

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

5. 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

6. 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

7. 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

8. 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)

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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. ESH/ESC Guidelines 2007: Recommended initial antihypertensive drug
Thiazide diuretics
β-blockers
ARB
α- blockers
CCB
ACEi

18. 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

19. 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)

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial The telmisartan trial in cardiovascular protection Sponsored by Boehringer Ingelheim

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

28. 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)

29. 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

30. Combinations Tested or Widely Used in Outcome (CV-renal events) Trials
ACEI / D
ACEI / CA
CA / BB
PROGRESS
ADVANCE
HYVET
LIFE
SCOPE
RENAAL
Syst-Eur
Syst-China
INVEST
ASCOT
HOT
ACCOMPLISH
FEVER
ELSA
VALUE
HOT (2nd used)
RENAAL (with D as well)
ARB / D
ARB / CA
CA / D

31. 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

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

33. Synergistic BP reduction Complementary clinical benefits
Conceptual Rationale for ARB +Ca antag.
Leveraging synergy of counter-regulation
Amlodipine
Arteriodilation
Peripheral edema
Effective in low-renin patients
Reduces cardiac ischemia
Valsartan
RAS blockade
CHF and renal benefits BP
Synergistic BP reduction
Complementary clinical benefits
Valsartan
Venodilation
Attenuates peripheral edema
Effective in high-renin patients
No effect on cardiac ischemia
Amlodipine
RAS activation
No renal or CHF benefits

34. 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

35. Avoiding Cardiovascular Events through COMbination Therapy in Patients LIving with Systolic Hypertension
Kenneth Jamerson1, George L. Bakris2, Bjorn Dahlof3, Bertram Pitt1,
Eric J. Velazquez4, and Michael A. Weber5
for the ACCOMPLISH Investigators
University of Michigan Health System, Ann Arbor, MI1; University of Chicago-Pritzker School of Medicine, Chicago, IL2; Sahlgrenska University Hospital, Gothenburg, Sweden3; Duke University School of Medicine, Durham, NC4; SUNY Downstate Medical College, Brooklyn, NY5 35

36. ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy90
81.7
78.5 80 70 60
Control rate (%) 50 40
Baseline Control Rates
37.2
37.9 30 20 10
ACEI / HCTZ
N=5733
CCB / ACEI
N=5713
P<0.001 at 30 months follow-up
Control defined as <140/90 mmHg

37. Kaplan Meier for Primary Endpoint
ACEI / HCTZ
CCB / ACEI
20% Risk Reduction
650
526
Cumulative event rate
p = 0 .0 2
Time to 1st CV morbidity/mortality (days)
HR (95% CI): 0.80 (0.72, 0.90)
INTERIM RESULTS Mar 08 37

38. Primary Endpoint and Components
Risk Ratio (95%)
Composite CV mortality/morbidity
Cardiovascular mortality
Non-fatal MI
Non-fatal stroke
Hospitalization for unstable angina
Coronary revascularization procedure
Resuscitated sudden death
0.5
1.0
2.0
0.80 (0.72–0.90)
0.81 ( )
0.81 ( )
0.87 ( )
0.74 ( )
0.85 ( )
1.75 ( )
Favors
CCB / ACEI
Favors
ACEI / HCTZ 38 38 38

39. 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)

40. 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

41. 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

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

43. 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

44. 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

45. 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

46. Blood Glucose Control in Diabetics
In hypertensive diabetic patients tight blood glucose control (HbA1C 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

47. 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 protection both in younger and in elderly patients

48. 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

49. 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

50. 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

51. 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

52. 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

53. 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.1.73m2
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

54. 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

55. 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

56. Atrial Fibrillation (AF) - Primary Prevention
In 2007 ESH / ESC guidelines recommendation to preferentially use ARBs / ACEIs
Evidence mainly from post-hoc analyses

57. 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

58. Atrial Fibrillation
In a meta-analysis on almost 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

59. 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 (?)

60. 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

61. 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

62. New Antihypertensive Drugs
Vasopressin antagonists
Neutral endopeptidase inhibitors
AT2 receptor agonists
Endothelin receptor antagonists
Renin inhibitors

63. Resistant hypertension: endothelin antagonist darusentan

64. Efficacy of darusentan

65. New Antihypertensive Drugs
Vasopressin antagonists
Neutral endopeptidase inhibitors
AT2 receptor agonists
Endothelin receptor antagonists
Renin inhibitors

66. 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.

67. Binding of renin inhibitors to the active site of renin

68. Mechanism of action of direct renin inhibitors

69. Renin Inhibition Reduces PRA and Other Components of RAS
Ang I
Ang II
Renin
PRA
ACEI ↑ ↓ ↑ ↑
ARB ↑ ↑ ↑ ↑ ↑
Diuretic ↑
Renin inhibitor ↓ ↓ ↑ ↓
Nussberger et al. J Hypertens 2002; Azizi et al. JASN 2004

70. Safety and Tolerability
Aliskiren
Irbesartan 150 mg
(n=134)
Placebo
(n=131)
150 mg
(n=127)
300 mg
(n=36.)
600 mg
(n=130)
Patients with AE (%)
Any AE
32.1
26.8
36.2
33.1
36.6
D/C due to AE
2.3
3.9
3.1
2.3
2.2
Serious AE
0.8 – – –
0.7
Most Frequent AEs (≥2%)
Headache
5.3
2.4
6.2
4.6
3.0
Diarrhea
Aliskiren demonstrated a safety and tolerability profile similar to that of placebo and irbesartan, with no evidence of a dose-dependent increase in the incidence of adverse events (AEs).
The percentage of patients reporting an AE was 26.8%, 36.2% and 33.1% with aliskiren 150 mg, 300 mg, and 600 mg, respectively, compared with 36.6% for irbesartan and 32.1% for placebo.
The number of patients discontinuing therapy due to AEs was similar in all groups (range 2.2–3.9%).
No serious AEs were reported in patients receiving aliskiren, and no deaths occurred in the study.
References
Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an AT1-receptor blocker in hypertensive patients. Am J Hypertens. 2004;17:108A. Abstract P-204.
1.5
1.6
0.8
6.9
1.1
Dizziness
3.8
1.6
3.1
2.3
3.7
Fatigue
3.1
0.8
3.8
1.5
1.5
Back pain –
1.6
2.3
1.5
4.5
Gradman AH et al. Circulation 2005;111:1012

71. Antihypertensive efficacy of the renin inhibitor aliskiren

72. New Trials Needed
Should antihypertensive drug treatment be prescribed in grade 1 HT (BP / 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?

73. 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?