Introduction

1. Comments on Reappraisal ofEuropean Guidelines on Hypertension Management: aEuropean Society of HypertensionTask Force DocumentV. GercClinic for heart disease andrheumatisam

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

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 mustinclude 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 EKGare 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 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

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 GuidelinesFirst Choice Drug Treatment * not to be initially preferred in patients at high risk of developing diabetes Diuretics* ACE-inhibitors Calcium antagonists Angiotensin receptor antagonists Beta-blockers*

17. ESH/ESC Guidelines 2007: Recommended initial antihypertensive drug Thiazide diuretics ARB β-blockers CCB α- blockers 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 tabletcombinations 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 TrialThe telmisartan trial in cardiovascular protectionSponsored by Boehringer Ingelheim

27. Indication and evidence forcombining ACEI and ARB

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 ARB / D ACEI / CA CA / D CA / BB ARB / CA 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)

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

33. 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 SynergisticBP reduction Complementaryclinical 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 inSyst-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 throughCOMbination 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

36. ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy 90 81.7 78.5 80 70 60 Control rate (%) 50 40 Baseline Control Rates 37.9 37.2 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 20% Risk Reduction ACEI / HCTZ 650 CCB / ACEI 526 Cumulative event rate p = 0 .0 0 0 2 Time to 1st CV morbidity/mortality (days) HR (95% CI): 0.80 (0.72, 0.90) INTERIM RESULTS Mar 08

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 0.80 (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) 2.0 0.5 1.0 Favors CCB / ACEI Favors ACEI / HCTZ

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

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 CVprotection 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