Resurgence of β-Blockers Across CV Continuum – Focus on

Hypertension
Prof. Emeritus Sverre E. Kjeldsen, MD, Dr. Med.
Department of Cardiology, Oslo University Hospital, Ullevaal, Oslo, Norway,
Division of Cardiovascular Medicine (adjunct), University of Michigan,
Ann Arbor, Michigan, USA
Past-President of the European Society of Hypertension
Editor-in-Chief Blood Pressure
COIs: Ad hoc lecture honoraria from Getz, Merck Healthcare KGaA, Sanofi, Takeda and Vector Intas
Antihypertensive Drugs and Outcomes in C-19

N=880
Severe Outcome n=415
(ICU or death)
(Mild Outcome n=465)

Eur Heart J - Cardiovasc Pharmacol 2020;6:415-416

Adapted From Vasanthakumar N. BioEssays 2020:42:2000094
 Prehypertension - 18 Year Follow-up
N 50. perc.
Blood pressure screening
19-year-old men 1. perc. 95-99. perc.
N = 4137
MBP
(mm Hg)

100 %
Prevalence of
hypertension after 18 80 %
years of follow-up
60 %

40 %
Hypertensives
20 %

Normotensives
0%

Flaa A, Kjeldsen SE et al. Hypertension 2008

 Arterial Plasma Noradrenaline During Mental Stress Predicts
Future High BP
Resting SBP at 18-Year Follow-Up

P=.004

SBP (mm Hg)

Arterial noradrenaline tertile at baseline during

mental stress test

Flaa A, Kjeldsen SE et al. Hypertension. 2008;32:336-341.

 Blood Pressure, Heart Rate and Plasma Catecholamines

Kjeldsen SE et al. Clin Sci 1981;61:215s-217s

 Arterial Plasma Catecholamines and Heart Rate
Correlations During Mental Stress
Males, High or Normal Screening BP (n=133)
2.0
1.5
1.0
ln NA (nmol/L) 0.5
0.0 r = 0.66
-0.5
p < 0.0001
-1.0
-1.5
3 4 5 6 7 8 9
ln A (pmol/L)
5.5 5.5
r = 0.66 r = 0.37
5.0 p < 0.0001 5.0 p < 0.0001
ln HR ln HR
4.5 4.5
(1/min) (1/min)
4.0 4.0

3.5 3.5
3 4 5 6 7 8 9 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0
ln A (pmol/L) ln NA (nmol/L)
Reims H, Kjeldsen SE et al, Blood Press 2005
Venous and Arterial Plasma Catecholamines
Untreated Hypertensives Versus Normotensives
50-Year Old Men From the Oslo Study

Noradrenaline (pg/mL) Adrenaline (pg/mL)

400 150
* ***
350 125
300
250 100
***
200 75
150 50
100
25
50
0 0
Venous Arterial Arterial Venous

*P <0.05, ***P <0.001 vs. NT NT (n=51)

HT (n=61)

Kjeldsen SE et al, Am Heart J 1989;118:775

 Mechanisms by
which high
plasma
adrenaline (Adr)
in people with
hypertension
(HT) may
further activate
sympathetic
activity by
stimulating
noradrenaline
(NA) release
Kjeldsen SE et al. Clin Sci 1981;61:215s-217s
 Treatment
based on
mostly
diuretics
and beta-
blockade

11
 Diuretic and beta-blocker treatment mainly

Prevention of Heart Failure and LVH in Hypertension

Strongly Suggests Similar Prevention of Atrial Fibrillation
12
13
14
 Drug Treatment Algorithm ESC/ESH 2018
The core algorithm is also appropriate for most patients with HMOD, cerebrovascular disease,
diabetes or PAD

Initial therapy Consider monotherapy in low-risk grade 1

1 pill ACEi or ARB + CCB or diuretic hypertension (systolic BP <150 mmHg), or in
Dual combination very old (≥80years) or frailer patients

Step 2
1 pill Triple combination ACEi or ARB + CCB + diuretic

Step 3 Resistant hypertension Consider referral to a specialist centre

2 pills Triple combination + Add spironolactone (25–50 mg OD) or other for further investigation
2 pills spironolactone or other drug diuretic, alpha-blocker or beta-blocker

Beta-blockers
Consider beta-blockers at any treatment step, when there is a specific indication for their use, e.g.
heart failure, angina, post-MI, atrial fibrillation, or younger women with or planning pregnancy

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor

2018 ESC/ESH Guidelines. Eur Heart J 2018;39:3021–3114
blocker; CCB, calcium channel blocker; OD: once a day; MI: myocardial infarction 2018 ESC/ESH Guidelines. J Hypertens 2018;36:1953–2041 16
2018 ESC/ESH Hypertension Guidelines Presentation at the ESH Meeting, Barcelona June 9th, 2018

Moving to Tailored Treatment/β-Bs Preferable in Several Conditions

Previous MI Acute coronary syndrome

Angina pectoris Thyrotoxicosis
Supraventricular Hyperkinetic syndrome
tachyarrhythmias Migraine
- Tachycardia Essential tremor
- Permanent AF
Perioperative hypertension
- Recurrent AF
Excessive pressor response to exercise (and
Ventricular arrhythmias
stress)
Glaucoma
Orthostatic hypertension
Pregnancy
Aortic aneurysm
Congestive heart failure
After CABG
Williams, Mancia et al., J Hypertens 2018;36:1953-2041 and Eur Heart J 2018;39:3021-3104
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
2018 ESC/ESH Hypertension 78
Guidelines

Drug Treatment Strategy for Hypertension

Recommendations Class Level
Among all antihypertensive drugs, ACE inhibitors, ARBs, beta-blockers, I A

CCBs, and diuretics (thiazides and thiazide-like such as chlorthalidone

and indapamide) have demonstrated effective reduction of BP and CV
events in RCTs, and thus are indicated as the basis of antihypertensive
treatment strategies.
Combination treatment is recommended for most hypertensive patients, I A

as initial therapy. Preferred combinations should comprise a RAS

blocker (either an ACE inhibitor or an ARB) with a CCB or diuretic. Other
combinations of the five major classes can be used.
It is recommended that beta-blockers are combined with any of the I A

other major drug classes when there are specific clinical situations, e.g.
angina, post-myocardial infarction, heart failure, or heart-rate control.

Williams, Mancia et al., J Hypertens 2018;36:1953-2041 and Eur Heart J 2018;39:3021-3104

 12

2018 ESC/ESH Hypertension Guidelines:

Factors influencing CV risk in patients with hypertension

Demographic characteristics and laboratory parameters
Sex (men > women)
Age
Smoking – current or past history
Total cholesterol and HDL-C
Uric acid
Diabetes
Overweight or obesity
Family history of premature CVD (men aged < 55 years and women aged < 65 years)
Family or parental history of early onset hypertension
Early onset menopause
Sedentary lifestyle
Psychosocial and socioeconomic factors
Heart rate (resting values > 80 beats per min)

Williams, Mancia et al., J Hypertens 2018;36:1953-2041 and Eur Heart J 2018;39:3021-3104

 CV and All-cause Mortality Survival Curve according to Time-varying
Persistence or Development of HR ≥ 84 bpm in ECG-LVH in LIFE

CV mortality All-cause mortality

15
Heart rate ≥ 84 Heart rate ≥ 84
10 Heart rate < 84
Heart rate < 84
8 10
% with event

4 5

0 0
0 12 24 36 48 60 0 12 24 36 48 60

Month Month

Okin PM, Kjeldsen SE, Julius S et al., Eur Heart J 2010; 31: 2271
VALUE: Prognostic Impact of In-Treatment Heart Rate

Julius S, Palatini P, Kjeldsen SE et al. AJC 2012; 109: 685-92

 Sympathetic overdrive in CAD & the target heart rate
ß-Blockers in Clinical Practice Guidelines:
Targeting Heart Rate Control <80 beats/min
Clinical setting Recommendation Evidence
Hypertension I A

Acute Myocardial Infarction / ACS I A

Secondary Prevention I A

Chronic Ischemia I A

Chronic Heart Failure I A

Arrhythmias I A

Sudden Death Prevention I A

ESC Guidelines 2016 www.escardio.org/guidelines

 All Cause Mortality
Sudden Cardiac Death

The Norwegian Timolol Study. Circulation 1982; 66: 1179-1184

Prognostic Value of Plasma NA in Asymptomatic Left
Ventricular Dysfunction (SOLVD)

Benedict CR et al. Circulation. 1996;94:690–

 Survival Studies of Beta Blockade in Heart Failure

N Favors Favors
Trial (beta blocker) Beta blocker placebo Risk reduction P

CIBIS-II (bisoprolol) 2647 34% .0001

MERIT-HF 3991 34% .00009
(ER metoprolol succinate)
COPERNICUS (carvedilol) 2289 35% .00013
BEST (bucindolol) 2708 10% .102

BEST, Beta Blocker Evaluation of Survival Trials.

0.0 0.5 1.0 1.5

Relative risk and 95% confidence interval

BEST Investigators. N Engl J Med. 2001;344:1659-1667; CIBIS-II Investigators. Lancet. 1999;353(9146):9-13; MERIT-HF Study
Group. Lancet. 1999;353(9169):2001-2007; COPERNICUS. Packer M, et al. N Engl J Med. 2001;344:1651-1658.
 CArvedilol Post-infaRct survIval COntRol in LV dysfunctioN

All Cause Mortality - Confirmed acute myocardial infarction

within 3 - 21 days (mean of 10 days)
1 - LV ejection fraction  40%
Proportion event free - Receiving an ACE inhibitor for  48 hours
0.95

0.9

Carvedilol
0.85

0.8

RR=0.77 (0.60-0.98), p=0.031 Placebo

0.75

0.7
0 0.5 1 1.5 2 2.5
Years
Lancet 2002;357:1385-1390
 MERIT - Total Mortality
Per cent Patients with Reduced EF (< 0.40) and Symptoms of Heart Failure (NYHA II-IV)
20

Placebo
15 p = 0.0062 (adjusted)
p = 0.00009 (nominal)
10
Metoprolol CR/XL

5
Risk reduction = 34%

0
0 3 6 9 12 15 18 21
Months of follow-up
29 The MERIT-HF Study Group, Lancet 1999;353:2001-07
Riemer TG et al. Hypertension 2021;77:1539-1548
2008 ESH Manual of Hypertension Chapter 46

Mistry NB, Westheim AS, Kjeldsen SE , ESH Textbook 2008

 Summary: First Line Treatment of Hypertension

• The European Hypertension Guidelines (ESC/ESH 2018)

recommend to start treatment with a combination of ACEi/ARB
plus CCB or diuretic (HCTZ, chlorthalidone, indapamide) in most
patients
• Consider beta-blockers at any treatment step, when there is a
specific indication for their use, e.g. heart failure, angina, post-MI,
atrial fibrillation, or younger women with or planning pregnancy
• Beta-blockers should be used for heart rate control (<80 beats/min)
in high risk hypertensive patients to prevent incident atrial
fibrillation, heart failure, CV mortality and all-cause death
 Northern Lights
(Winter view from the
island of Senja south of
Tromsø, NORWAY)

Oslo RDN study

Back-up Slides
 Heart Rate and BP as Predictors of Hypertension

Levy RL, et al. JAMA. 1945.

 Autonomic Imbalance Raises Heart Rate in Neurogenic Pre-Hypertension.

120 5.0

110 4.5

Cardiac Index (I/min/m2)

Heart Rate (bpm)

100 4.0

90 3.5

80 3.0

70 2.5
Borderline Hypertension
60 Control Subjects
2.0

Rest Propranolol Atropine Rest Propranolol Atropine

Julius S, et al. Circulation. 1971;44:413–418.

MSNA ad modum Björn Gunnar Wallin
(Gothenburg, Sweden)
 Heart Rate as a Marker of Sympathetic Activity
10 Minutes Supine ECG Recordings (n = 243)

NA (pg/mL) MSNA (bursts/min)

1600 rs = 0.32 100 rs = 0.38
P <0.0001 80 P <0.0001
1200
60
800
40
400
20
0 0
40 50 60 70 80 90 100 110 40 50 60 70 80 90 100 110
Heart Rate (beats/min) Heart Rate (beats/min)

MSNA = muscle sympathetic nerve activity (peroneal)

NA = venous plasma noradrenaline (antecubital)
rs = Spearman’s Correlation Coefficient
Grassi G et al. J Hypertens 1998;16:1635
 The VALUE trial: Kaplan-Meier Curves for Primary Events
by In-trial Heart Rate (year 1) and Level of BP Control (year 1)

14
5th HR quintile and uncontrolled BP Uncontrolled BP /
Other 4 quintiles with uncontrolled BP Highest HR quintile
Cumulative primary event rate

12 5th HR quintile and controlled BP Controlled BP /

Other 4 quintiles with controlled BP Highest HR quintile
10 Uncontrolled BP /
Lowest HR quintiles
8 Controlled BP /
Lowest HR quintiles

2
BP control < 140/90 mmHg
0
0 250 500 750 1000 1250 1500
Days since year 1

Julius S, Palatini P, Kjeldsen SE et al. Am J Cardiol 2012; 109: 685-692

 2018Hypertension
2018 ESC/ESH ESC/ESH Hypertension
Guidelines 79 June 9th, 2018
Presentation at the ESH Meeting, Barcelona
Guidelines
Drug treatment strategy for hypertension
Recommendations Class Level
It is recommended to initiate an antihypertensive treatment with a two- I B

drug combination, preferably in a SPC. Exceptions are frail older patients and
those at low risk and with grade 1 hypertension
(particularly if SBP is < 150 mmHg).

It is recommended that if BP is not controlled with a two-drug combination, I A

treatment should be increased to a three-drug

combination, usually a RAS blocker + CCB + thiazide/thiazide-like diuretic,
preferably as an SPC.
It is recommended that if BP is not controlled with a three-drug I B

combination, treatment should be increased by the addition of spironolactone or, if

not tolerated, other diuretics such as amiloride or higher doses of other diuretics, a
beta-blocker, or an alpha-blocker.
The combination of two RAS blockers is not recommended. III A

Williams, Mancia et al., J Hypertens 2018;36:1953-2041 and Eur Heart J 2018;39:3021-3104

Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
2018 ESC/ESH Hypertension Guidelines Presentation at the ESH Meeting, Barcelona June 9th, 2018

Beta-Blockers in Combination Treatment

Beta-blockers in combination to be preferentially used in:

- Symptomatic angina
- Heart rate control (<80 beats/min)
- Post-myocardial infarction
- Atrial fibrillation
- Heart failure
- Women with child-bearing potential/planning pregnancy

Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
 Classification of beta-blockers according to their beta1-selectivity1,2

Relative beta1-selectivity Non-selective Beta1-selective

• Bupranolol • Atenolol
• Propanolol • Metoprolol
• Timolol • Bisoprolol
• Labetalol • Betaxolol
• Carvedilol • Esmolol
• Alprenolol
• Pindolol • Acebutolol
Intrinsic sympathomimetic
• Oxprenolol • Celiprolol
activity (ISA)
• Carteolol • Nebivolol
• Bucindolol
• Nadolol • Atenolol
Hydrophilia
• Sotalol • Celiprolol

1. Egan BM, Basile J, Chilton RJ et al. Cardioprotection: the role of beta-blocker therapy. J Clin Hypertens. 2005;7(7):409­–16.
2. López-Sendón J, Swedberg K, McMurray J et al. for the Task Force on Beta-blockers of the European Society of Cardiology.
Expert consensus document on beta-adrenergic receptor blockers. Eur Heart J. 2004;25:1341-62.
3. 45
Cruickshank J. Nebivolol, a third generation beta-blocker. J Symptoms Signs. 2014;3(5):380-91
 Primary Prevention: MAPHY1,2
3234 men 40–64 years old randomized to beta-blocker or thiazide diuretic

Thiazide diuretics (n=1625) Beta-blocker (n=1609)

Total mortality Sudden CV death

90 50
80
70 40
Cumulative 60
30
number of 50
deaths 40
20
30 RRR 22% RRR 30%
20 P=0.028 10 P=0.017
10
0 0
0 5 10 0 5 10
Years Years
MAPHY, Metroprolol Athersclerosis Prevention in Hypertensives; RRR, relative risk reduction

Olsson G et al. Am J Hypertens.1991;4:151-158. Wikstrand J et al. JAMA.1988;259:1976-1982.

Reduction of Stroke in Hypertension Related to Reduction in Blood Pressure

Turnbul F. Lancet 2003;362:1527-1535, Dahlöf B, Kjeldsen S, et al. Lancet 2005;366:895-906.