Yves Allemann

Cardiologie Pré-Vert

1630 Bulle

Roman Brenner

Kardiologie Kantonsspital

St.Gallen

Therapy of Hypertension in Patients With

Coronary Heart Disease

EUROASPIRE

Koronariker mit unkontrolliertem BD (>140/90 resp 130/80mmHg)

0%

20%

40%

60%

80%

100%

Euroaspire I Euroaspire II Euroaspire III

1995-1996 1999-2000 2006-2007

SWISSHYPE 2009

0%

5%

10%

15%

20%

KHK St. n. MI AP Revask

Hypertoniker mit KHK in Hausarztpraxen

KHK

Keine AP/Ischämie

St. n. Infarkt OHNE LV

DysfunktionArrhythmien

Angina pectoris / Ischämie

Herzinsuffizienz (LVEF )

Relevante Koronarstenose

Maeder, Praxis 2009

INFARKT

HERZINSUFF

ESH Guidelines 2013: BBl bei KHK prominent

Essenzielle Hypertonie - SHG

Antianginosa

• Negativ inotrop, negativ chronotrop

• Diastolische Füllungszeit der Koronarien wird verlängert (HF nimmt ab)

Antianginosa

• Vasodilatation (koronar, peripher)

• NDHP: Negativ chronotrop, inotrop

CCB bei Ischämie

• Indikation– Wenn BBl kontraindiziert, nicht tolerabel oder ungenügend

wirksam (AHA IIa B)

• Vorsicht– In Kombi mit BBl: lang wirksame DHP zu bevorzugen vor

NDHP (Bradykardie!)– Keine NDHP bei HF oder LV Dysfunkt.– Keine kurzwirksamen DHP (reflektorische Aktivierung des

Sympathikus und Zunahme der Ischämie)

Fall 1, Mann 68y

• KHK-2, St. n. PCI RCx vor 5 Jahren (AP)

• Kein DM

• 161/92mmHg, HF 55/min, beschwerdefrei

• Echo: LVEF 60%, keine Wandbewegungsstörungen

• ASS, Statin, Concor 5mg

Was machen Sie?• +Perindopril

• +Kombination ACE-I / Thiazid

• Betablocker erhöhen, ACE-I zusätzlich

• +Kombination CCB / ACE-I

ACCOMPLISH Studie (2008)• Population

– 11506 Pt mit aHT und hohem cv Risiko– Mittl. BD 145/80mmHg, 60% DM, 73% Dyslip.– 23% früherer MI, 36% koronare Revask, 13% stroke– 47% Betablocker, 65% Tc-Aggreg.hemmer

• Intervention– Randomisiert Benazepril-HCT vs Benazepril-Amlo

• Resultat– Prim. Endpunkt: cv Ereignis und

Cv Tod

– Früzeitiger Studienstop wegen Über-legenheit

HR 0.8 (0.72-0.9)

PROGNOSTISCHE Indikationen RAS-I +/- Infarkt ohne LV-Dysfunktion

ESC SIHD 2013 It is recommended to use ACE inhibitors (or ARBs) if presence of other conditions (e.g. heart failure, hypertension or diabetes) [HOPE, EUROPA] (IA)

ESC NSTEMI 2015 ACE inhibitors are recommended in patients with systolic LV dysfunction or heart failure, hypertension or diabetes (agents and doses of proven efficacy should be employed). ARBs are indicated in patients who are intolerant of ACE inhibitors [HOPE, ONTARGET, EUROPA]

ESC STEMI 2012 ACE inhibitors should be considered in all patients in the absence of contraindications [HOPE, EUROPA]. (IIa A)

Use of ACE inhibitors should be considered in all patients with atherosclerosis, but, given their relatively modest effect, their long-term use cannot be considered mandatory in post-STEMI patients who are normotensive, without heart failure, or have neither LV systolic dysfunction nor diabetes.

AHA / ACC SIHD ACE inhibitors should be prescribed in all patients with SIHD who also have hypertension, diabetes mellitus, LVEF 40% or less, or CKD, unless contraindicated [HOPE, EUROPA] (I A).

AHA / ACC STEMI 2004 An ACE inhibitor should be prescribed at discharge for all patients without contraindications after STEMI. (I A)

An ACE inhibitor should be administered orally during convalescence from STEMI in patients who tolerate this class of medication, and it should be continued over the long term. (I A)

Drug-drug comparison: CCB bei stabiler KHK

• INVEST: – 22576 Pt mit stabler KHK und HT. – Verapamil vs Atenolol. – Kein Unterschied prim Endpunkt (Tod + MACE)

• ALLHAT bei KHK: – Pt mit KHK aus ALLHAT– Amlo vs Lisinopril weniger stroke, weniger Sterblichkeit (p=0.06)

• CAMELOT: – Pat mit KHK– Amlo vs Enalapril– weniger cv events bei Amlo

• VALUE: – 46% KHK– Amlo vs Valsartan prim Endpunkt=, weniger MI und stroke unter Amlo

• Kein Mortalitätsunterschied verglichen mit Kontrollen (Antihypertensiva und Placebo)

• Signifikant weniger stroke, v.a. Amlo

Fall2: Mann, aktiv, 73y • St. n. inferiorem Infarkt vor 2 Jahren, RCA-Intervention• Arterielle Hypertonie seit 12 Jahren, unter Lisinopril, später

Lisinopril HCT• Echo: LVEF 50%, inferolaterale Hypokinesie• Beschwerdefrei, keine AP, BD 132/81mmHg• möchte Betablocker wieder absetzen wegen

Leistungsminderung und Impotenz• Medikamente

– Lisinopril HCT 20/12.5 1-0-0; Concor 5 1-0-0; ASS; Atorva 40mg

• Was machen Sie?– Betablocker ausschleichen und absetzen, ev. Ersatz durch CCB

bei BD >140/90mmHg– Betablocker weiterhin indiziert. Zieldosis essenziell. Zum

Urologen schicken.– Betablocker belassen, Dosis reduzieren. HCT absetzen. CCB

wenn BD >140/90

• Was würden Sie machen, wenn der Patient ein NSTEMI gehabt hätte?

PROGNOSTISCHE Indikationen BBl nach Infarkt ohne LV-Dysfunktion

AHA / ACC SIHD 2012 IB: Beta-blocker therapy should be started and continued for 3 years in all patients with normal LV function after MI or ACS [1-3].

Iib C: Beta blockers may be considered as chronic therapy for all other patients with coronary or other vascular disease.

AHA / ACC STEMI 2004

IA: All patients after STEMI except those at low risk (normal or near-normal ventricular function, successful reperfusion, and absence of significant ventricular arrhythmias) and those with contraindications should receive beta-blocker therapy. Treatment should begin within a few days of the event, if not initiated acutely, and continue indefinitely.

Iia A: It is reasonable to prescribe beta-blockers to low-risk patients after STEMI who have no contraindications to that class of medications [6].

AHA / ACC STEMI Update 2007

IA: It is beneficial to start and continue beta-blocker therapy indefinitely in allpatients who have had MI, acute coronary syndrome, or LV dysfunction with or without HF symptoms, unless contraindicated (I A).

AHA /ACC NSTEMI 2007

IB: Patients after non low-risk NSTEMI. Continued indefinitelyIIaB: Patients after low-risk NSTEMI (normal LVEF, revascularized, no high-risk features)

PROGNOSTISCHE Indikationen BBlnach Infarkt ohne LV-Dysfunktion

ESC SIHD 2013 No recommendation for event prevention

ESC STEMI 2012 Iia B: Oral treatment with beta-blockers should be considered during hospital stay and continued thereafter in all STEMI patients without contraindications [3, 4].

The benefit of long-term treatment with beta-blockers after STEMI is well established, although mostly from trials pre-dating the advent of modern reperfusion therapy and pharmacotherapy.

ESC NSTEMI 2015 No recommendation. Betablocker therapy has not been investigated in contemporary RCTs in patients after NSTE-ACS and no reduced LV function or heart failure. In a large-scale observational propensity-matched study in patients with known prior MI, beta-blocker use was NOT associated with a lower risk of CV events or mortality [5].

[3]: Freemantle et al: Beta Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ. 1999;318:1730 –7[4]: COMMIT

COMMIT Studie [4]• Population

– 45852 Patienten mit STEMI– Patienten mit geplanter PCI wurden ausgeschlossen – 50% lysiert. Mittl. SBP 128mmHg

• Intervention – randomisiert Metoprolol (bis 15mg iv, dann 200mg po) vs Placebo

• FU-Zeit – bis Spitalentlassung (max. 4 Wochen)

• Outcome: – Prim. EP: Tod, Reinfarkt oder cardiac arrest: kein Unterschied– -0.5% weniger Reinfarkte (p<0.001), -0.5% weniger VF (p<0.001), +1.1%

kardiogener Schock (p<0.00001)

Ozasa, J-CYPHER Register • Population

– 910 STEMI Patienten nach PCI

• Intervention– Gruppiert nach BBl ja (n=349)/nein bei Austritt

• FU-Zeit– 3 Jahre

Propensity score matching:Adjustierte HR: 1.1 (0.6-1.9)

Propensity score matching:Adjustierte HR: 1.1 (0.8-1.7)

Goldberger, OBTAIN-Register• Population

– 7057 Patienten mit AMI (60% NSTEMI)

• Intervention– Gruppierung der Betablocker-Dosis (% der Zieldosierung) bei Spitalentlassung

• FU-Zeit– Median 2.1 Jahre

• Outcome– Mortalität

n.s.

Absence of a special effect of BBL in theabsence of a recent infarct

Law, BMJ 2009

European Society of Hypertension (ESH) / European

Society of Cardiology (ESC)

2007 Guidelines for the Management of Arterial Hypertension

J Hypertens 2007, 25:1105-

Target BP should be at least <130/80 mmHg in:

• Diabetics

and in high or very high risk patients, such as those with associated

clinical conditions:

• Stroke

• Myocardial infarction

• Renal dysfunction / proteinuria

Reappraisal of European Guidelines on Hypertension Management

Journal of Hypertension 2009

The recommendation of previous guidelines to aim at a lower goal SBP

(<130 mmHg) in diabetic patients and in patients at very high CV risk

(previous cardiovascular events) may be wise, but it is not consistently

supported by trial evidence.

… and trials in which SBP was lowered to <130 mmHg in

patients with previous cardiovascular events have given controversial

results.

On the basis of current data, it may be prudent to recommend lowering

SBP/DBP to values within the range 130-139 / 80-85 mmHg, and possibly

close to lower values in this range, in all hypertensive patients.

2013 ESH/ESC Guidelines for the management of arterial hypertension

Blood Pressure Goals

Journal of Hypertension 2013, 31:1925–1938

2013 ESH/ESC Guidelines for the management of arterial hypertension

Blood Pressure Goals

Journal of Hypertension 2013, 31:1925–1938

2013 ESH/ESC Guidelines for the management of arterial hypertension

Blood Pressure Goals

Journal of Hypertension 2013, 31:1925–1938

… on the contrary, a number of the correlative analyses raising

suspicion about the existence of a J-curve relationship between

achieved BP and CV outcomes included a high proportion of CHD

patients and it is not unreasonable that, if a J-curve occurs, it may

occur particularly in patients with obstructive coronary disease.

Fallbeispiel

Frau, 71 Jahre

Guter Allgemeinzustand, BMI 27.1

Langjährige art. Hypertonie und bekannte KHK.

Therapie: ACE-Hemmer, Thiazid, Betablocker,

Statin, Aspirin

Symptome: Zunehmende Müdigkeit und Schwindel im Verlauf

des Nachmittags manchmal auch von «Druck auf der Brust»

begleitet.

Praxis BD im Durchschnitt : 168/68 mmHg

Blood Pressure Patterns in the General Population

30-39 40-49 50-59 60-69 70-79 > 80

70

80

110

130

150

Age

DBP

SBP

30-39 40-49 50-59 60-69 70-79 > 80

70

80

110

130

150

Age

DBP

SBP

Adapted from: Third National Health and Nutrition Examination Survey, Hypertension 1995;25:305-313

Men Women

Burt V L et al. Hypertension 1995;25:305-

150

110

70

30-39 50-59 70-79

Systolic BP

Diastolic BP

[mm Hg]

Age [years]

PP = SBP-DBP

Estimation of Arterial Stiffness: Pulse Pressure

Franklin et al., Circulation 1999; 100:354-

Pulse Pressure and CV Risk

3

2

1

CHD Hazard ratio

Pulse pressure (PP)

40 60 80 100

Fallbeispiel

Frau, 71 Jahre

Guter Allgemeinzustand, BMI 27.1

Langjährige art. Hypertonie und bekannte KHK.

Therapie: ACE-Hemmer, Thiazid, Betablocker,

Statin, Aspirin

Symptome: Zunehmende Müdigkeit und Schwindel im Verlauf

des Nachmittags manchmal auch von «Druck auf der Brust»

begleitet.

Praxis BD im Durchschnitt : 168/68 mmHg

Que faites vous?

Augmentation du ttt antihypertenseur?

(168/68 mmHg)

MAPA?

ECG?

Test d‘effort?

Echocardiographie?

Coronarographie?

Off

ice

BP

176/8

2

mmHg

180

150

120

90

60

30

12h 15h 18h 21h 00h 03h 06h 09h

Ambulatory BP

Average 24 hr: 132/78 mmHg

ECG

Fallbeispiel

Fallbeispiel

Coronary Perfusion Pressure:

Epicardial coronary artery stenosis

LV Hypertrophy / Diastolic dysfunction

Myocardial

Ischemia

LV Diastolic

Dysfunction

Left Ventricular

End Diastolic

Pressure

Coronary

Pressure

Gradient

Incidence of MI and Stroke Stratified by Diastolic BP in INVEST

Messerli FH, Ann Intern Med. 2006;144:884-

Incidence of Myocardial Infarction (%)

Incidence of Stroke (%)

Diastolic BP

[mmHg]

What is the Optimal Blood Pressure

in Patients After Acute Coronary Syndromes?[PROVE IT-TIMI 22 Trial]

Bangalore S, Circulation 2010;122;2142-

*Composite: death, MI, unstable angina, stroke ,

revascularization after 30 days

Incid

en

ce

of

Ou

tco

me

* (%

) Nadir: 85 mmHg

Treating to New Targets

Blood Pressure and Non-Fatal Myocardial Infarction

Bangalore S, European Heart Journal (2010) 31, 2897-

60 70 80 90 100 110 120 130 140 150 160 170

Diastolic BP, mmHg Systolic BP, mmHg

INVEST

Analysis of clinically significant interactions of baseline covariates

and diastolic BP for the primary outcome*

Messerli FH, Ann Intern Med. 2006;144:884-

Diastolic BP, mmHg Diastolic BP, mmHg

Ha

za

rdR

ati

o

*all-cause death, nonfatal stroke and nonfatal myocardial infarction

o with revascularization

⦁ without revascularization

Fallbeispiel

Langjährige art. Hypertonie und bekannte

symptomatische KHK.

Therapie:

ACE-Hemmer

Thiazid

Betablocker

Statin

Aspirin

Antihypertensive Drugs in Hypertensive Patients With CAD

Aronow WS, JACC 2011; 57:2037–114

Drug Class Associated Clinical Condition

Betablockers Secondary prevention

Angina

Arrhythmia

ACE-Inhibitors

ARB

Secondary prevention

Systolic LV Function (<40%)

Heart failure

LV Hypertrophy

Diabetes

Verapamil

Diltiazem

Secondary prevention

Angina

Arrhythmia

Dihydropyridine CCB Angina

Persistent high BP

Aldosterone-Antagonists Systolic LV Function (<40%)

Heart failure

Diuretics Persistent high BP

Hypervolemia

Relative risk estimates of coronary heart disease events in

single drug BP difference trials according to class of drug*

*excluding CHD events in trials of β blockers in people with a history of coronary heart disease

Law MR, BMJ 2009;338:b1665

Relative risk estimates of coronary heart disease events in 46 drug comparison

trials comparing each of the five classes of BP lowering drug with any other class of

drug*

*excluding CHD events in trials of β blockers in people with a history of coronary heart disease

Law MR, BMJ 2009;338:b1665

Fallbeispiel

Ziel Blutdruck???

< 140 / 90 mmHg

< 140 / 85 mmHg

< 130 / 80 mmHg

The <140/90 mmHg BP target is reasonable for the secondary prevention

of cardiovascular events in patients with hypertension and CAD.

(Class IIa; Level of Evidence B)

Hypertension 2015

BP target <140/90 mmHg

Hypertension 2015

A lower target BP (<130/80 mmHg) may be appropriate in some individuals

with CAD, previous MI, stroke or transient ischemic attack, or CAD risk

equivalents (carotid artery disease, PAD, abdominal aortic aneurysm).

(Class IIb; Level of Evidence B)

BP target <130/80 mmHg

Take-Home Messages

In hypertensive patients with (suspected) coronary artery disease:

├ Coronary perfusion occurs in diastole

├ J-curve, particularly for diastolic BP

├ J-curve for diastolic BP is organ-specific (heart)

├ High-risk patients: elderly ± LVH ± wide pulse pressure

├ Goal BP: 140 / 90 mmHg

Goal BP: 130 / 80 mmHg (may be appropriate in some individuals with CAD)

├ Indicated drug classes are: Betablockers (Verapamil, Diltiazem), ACE-

Inhibitors or ARBs.