Transcript CASE REPORTS - Udruženje kardiologa Bosne i Hercegovine

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
%
%
Goal systolic/diastolic
BP, mm Hg
Systolic
BP
Diastolic
BP
Uncomplicated
< 140/90
64
26
Black
< 140/90
62
37
Elderly
< 140/90
78
9
Diabetic
< 130/85
81
24
Patient
subgroup
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
ARB
β-blockers
α- blockers
CCB
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
ONgoing Telmisartan Alone
and in combination with
Ramipril Global Endpoint
Trial
The telmisartan trial in cardiovascular
protection
Indication and evidence for
combining ACEI and ARB
Indication
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
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
ACEI / CA
CA / BB
PROGRESS
ADVANCE
HYVET
Syst-Eur
Syst-China
INVEST
ASCOT
HOT
ACCOMPLISH
HOT (2nd used)
ARB / D
LIFE
SCOPE
RENAAL
ARB / CA
CA / D
FEVER
ELSA
VALUE
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 ?
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
ACEI+diuretic
Lisinopril + HCTZ
Prinzide
ACEI+CCB
Benazepril + amlodipine
Lotrel
ACEI+CCB
Enalapril + felodipine
Lexxel
ACEI+CCB
Trandolapril + verapamil
Tarka
BB+diuretic
Atenolol + chlorthalidone
Tenoretic
ARB+diuretic
No ARB+CCB
Conceptual Rationale for ARB +Ca
antag.
Leveraging synergy of counter-regulation
Amlodipine
 Arteriodilation
 Peripheral edema
 Effective in low-renin patients
 Reduces cardiac ischemia
Valsartan
 Venodilation
 Attenuates peripheral edema
 Effective in high-renin patients
 No effect on cardiac ischemia
BP
Synergistic
BP reduction
Complementary
clinical benefits
Valsartan
 RAS blockade
 CHF and renal
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 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
ACCOMPLISH: Exceptional Control Rates
with Initial Combination Therapy
90
Control rate (%)
80
78.5
81.7
70
60
50
40
30
37.2
37.9
ACEI / HCTZ
CCB / ACEI
N=5733
N=5713
20
10
P<0.001 at 30 months follow-up
Control defined as <140/90 mmHg
Baseline
Control Rates
Kaplan Meier for Primary
Endpoint
Cumulative event rate
ACEI / HCTZ
20% Risk Reduction
650
CCB / ACEI
526
p = 0 .0002
Time to 1st CV morbidity/mortality (days)
HR (95% CI): 0.80 (0.72, 0.90)
INTERIM RESULTS Mar 08
Primary Endpoint and
Components
Risk Ratio
(95%)
Composite CV mortality/morbidity
0.80 (0.72–0.90)
Cardiovascular mortality
0.81 (0.62-1.06)
Non-fatal MI
0.81 (0.63-1.05)
Non-fatal stroke
0.87 (0.67-1.13)
Hospitalization for unstable angina
0.74 (0.49-1.11)
Coronary revascularization procedure
0.85 (0.74-0.99)
Resuscitated sudden death
1.75 (0.73-4.17)
0.5
Favors
CCB / ACEI
1.0
2.0
Favors
ACEI / HCTZ
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
Acceptable 2-drug
Unacceptable 2-
combinations
drug combinations
ACE
inhibitor/diuretic*
Beta-blocker/diuretic*
ACE inhibitor/ARB
ARB/diuretic*
CCB/diuretic
ACE inhibitor/beta
blocker
ACE inhibitor/CCB* Renin
ARB/beta blocker
inhibitor/diuretic
ARB/CCB*
Thiazide
diuretic/potassiumsparing 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 (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
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
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.1.73m2
• 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
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
• AT2 receptor agonists
• Endothelin receptor antagonists
• Renin inhibitors
Resistant hypertension: endothelin
antagonist darusentan
Efficacy of darusentan
New Antihypertensive Drugs
• Vasopressin antagonists
• Neutral endopeptidase inhibitors
• AT2 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
Aliskiren
Placebo 150 mg
Patients with AE (%) (n=131) (n=127)
Any AE
32.1
26.8
300 mg
(n=36.)
36.2
600 mg
(n=130)
33.1
Irbesartan
150 mg
(n=134)
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
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
–
1.6
2.3
1.5
4.5
Back pain
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?