Role of beta blocker and statin in primary prevention of cardiovascular disease

1. Role of Beta Blocker and Statin
in Primary Prevention
Dr Awadhesh Kr Sharma, DM,FACC,FSCAI
Assistant Professor
LPS Institute of Cardiology,
GSVM Medical College, Kanpur, UP,INDIA
E-mail: awakush@gmail.com

2. Patient profile
 A 37 years male patient working in corporate company attended OPD
with c/o headache, discomfort in chest.
 History:- Type 2 diabetes mellitus, hypertensive (10 years), non-
alcoholic, smoker-15 years, with history of dyslipidemia.
 Family history:- Father – had multi vessel coronary artery disease,
CABG done-20 years back, on medication.
Case study discussion is for education
purpose only

3.  On examination: Conscious. Pulse-99/min (regular), BP- 150/80 mmHg. Old ABPM report (3
month back)- morning surge of SBP ,Resp Rate-19/min. SpO2-97%.
 Blood exam (1 month old report)- Hb-11 g/dl, LDL- 168mg/dl, TG-210 mg/dl, HDL-31 mg/dL,
serum Cr-1.2 mg/dl (72 ml/min –MDRD). LFT (on spot)- Normal limit
 On spot ECG- sinus tachycardia, rest within normal limit.
 On spot & serial cardiac biomarker reports- Trop T-negative.
 2D ECHO suggestive of concentric LVH/No RWMA/LVEF 60%.
 Serum Glucose spot-170 mg/dl, ABG- normal parameters. Electrolytes- within normal range
 Medication: Antihypertensive (Telmisartan 40 mg with hydrochlorothiazide-OD , Amlodipine 5
mg- OD,, Rosuvastatin 5 mg –OD. Metformin 500 mg OD, Empagliflozin 10 mg OD.
 A possible case of dyslipidemia ,diabetes mellitus, hypertension with sympathetic surge at
present.
Patient profile
Case study discussion is for education
purpose only

4. 62.4
37.6
Indian Heart J. 2014 Nov-Dec; 66(6): 686–690.
 >62% Indian Hypertensives are having
Sympathetic surge or over-activity

5. Influence of
sympathetic
overactivity
on various
systems
Indian Heart J. 2014 Nov-Dec; 66(6): 686–690.

6. Sympathetic overdrive plays a key role in the pathophysiology of
cardiovascular disease
Egan BM, Basile J, ChiltonRJ et al. Cardioprotection: the roleof β-blockertherapy. J Clin Hypertens.
2005;7(7):409–16
The degree of SNS activation, as measured by plasma norepinephrine, was independently
associated with increased risk of death in the Vasodilator Heart Failure Trial II (V‐HeFT II).
Faster HRs may increase pulsatile stresses on the vascular system,
particularly at branch points, and may augment atherosclerotic lesions, and perhaps plaque rupture.
Higher HRs were associated with a roughly 2.2‐fold greater risk for
all‐cause mortality and 1.7‐fold higher CV mortality.

7. Sympathetic activity is elevated in patients
with diabetes and hypertension
Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011; Fig. 3-8

8. Sympathetic Nervous system is overactive in
Congestive heart
failure,
Acute myocardial
infarction,
Ischemic stroke,
Hypertension,
Renal failure
Sympathetic
deactivation
should be an
important goal of
pharmacologic
treatment in these
diseases.
1.European Society of Cardiology, Journals, e-Journal of Cardiology Practice, E-Journal of Cardiology Practice - Volume 5;
escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-5/Sympathetic-Activation-and-Prognosis-in-Cardiovascular-
Disease-Title-Sympathe last access 19th Dec 2019

9. 9
This Hypertensive patient with symptoms of Sympathetic
Overactivity, and being Dyslipidemic, need
Beta-blocker Statin

10. Beta blockers
Beta-receptor blockers have been around for more
than 35 years in cardiovascular medicine.
Beta-receptor blocker therapy has shown evidence of
benefit, for example, with metoprolol in prevention
of carotid intima media thickness progression in the
BCAPS trial.
Nilsson, P., Berglund, G. Beta-receptor blockers in primary prevention for cardiovascular disease: forgotten benefits?. J Hum Hypertens 20,
719–721 (2006). https://doi.org/10.1038/sj.jhh.1002042

11. Beta blockers
 Beta-Blockers should be first-line therapy for hypertensive
patients up to the age of 65 years, particularly men (and
nonsmokers) as Q-wave myocardial infarction is significantly
decreased by beta-blockers .
 Beta-blockers may prevent first events of nonfatal myocardial
infarction in patients with high blood pressure.
 Higher doses of beta-blockers conferred greater protection.
Psaty BM, Koepsell TD, LoGerfo JP, Wagner EH, Inui TS. Beta-blockers and primary prevention of coronary heart disease in patients with high
blood pressure. JAMA. 1989;261(14):2087-2094.

12. Beta blockers
β blockers, particularly those without intrinsic
sympathomimetic activity (ISA), reduce
sudden cardiac deaths by 30% or more in
select groups of hypertension, HF, and post‐MI
patients.

13. Beta blocker trials in primary prevention
 In the Assessment of Treatment With Lisinopril and Survival (ATLAS) study, HF
patients with higher HR were at increased risk for all‐cause mortality, CV death,
sudden death, and HF death.
 Beta‐blocker use in ATLAS was associated with a reduction in sudden death.
 The Cardiac Insufficiency Bisoprolol Study II (CIBIS‐II) showed that HR reduction at
2 months was associated with improved survival and reduced hospital admissions.
 Lower HRs were also associated with decreased morbidity and mortality in the
Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure
(MERIT‐HF) .

14. Beta blocker in primary prevention
 Beta blockers have antihypertensive, antiarrhythmic, and anti‐ischemic effects, and there is some
evidence for antiatherogenic effects.
 Beta blockers inhibit sympathetic outflow centrally, slow HR, decrease cardiac contractility, and
reduce renin‐angiotensin‐aldosterone system activity by inhibiting renin release.
 Compared with other antihypertensives, β blockers have the greatest combined effect on reducing
BP, HR, and myocardial contractility, which are three major determinants of myocardial O2
consumption.
 Beta blockers reduce tachyarrhythmias associated with sudden death.
 By lowering HR and contractility, β blockers reduce the pulsatile forces of blood flow within the
arterial system, which may decrease the risk of plaque rupture.
Brent M. Egan MD Jan Basile MD Robert J. Chilton DO Jerome D. Cohen MD. Cardioprotection: The Role of β‐Blocker Therapy.The journal of
clinical hypertension. Volume7, Issue7,July 2005,Pages 409-416.https://doi.org/10.1111/j.1524-6175.2005.04486.x

15. Beta-blockers In The Management Of Hypertension and controlling morning surge and sympathetic overactivity..
 Once-daily atenolol does not
provide adequate blood pressure
control during the night-time and
early morning periods because of
its pharmacokinetic profile and
half-life .
 On the other hand, metoprolol
has shown to be more effective in
sustaining 24-hour and early
morning BP reductions as
compared with atenolol .
Hirofumi Tomiyama and Akira Yamashina, “Beta-Blockers in the Management of Hypertension and/or Chronic Kidney Disease,” International
Journal of Hypertension, vol. 2014, Article ID 919256, 7 pages, 2014.
P. Sarafidis, Z. Bogojevic, E. Basta, E. Kirstner, and G. L. Bakris, “Comparative efficacy of two different beta-blockers on 24-hour blood pressure control,” The
Journal of Clinical Hypertension, vol. 10, no. 2, pp. 112–118, 2008.

16. Uniqueness of Metoprolol
Half life- 3-4 hours.
Excretion through Hepatic Route.
Metoprolol is rapidly and completely absorbed
throughout the GI-tract, including the distal
regions.
Eur J Clin Pharmacol (1988) 33 [Suppl]: 3-S7

17. Metoprolol is preferred even in low eGFR patient
 In patients with CKD, the accumulation of beta-blockers or active metabolites could
exacerbate concentration-dependent side effects such as bradycardic arrhythmias1
1. Frishman WH, Alwarshetty M. Beta-adrenergic blockers in systemic hypertension: pharmacokinetic considerations related to the
current guidelines. Clin Pharmacokinet 2002; 41: 505–516.
Beta-blocker Half
life
(hrs)
Dose-
dependent
bioavailability
(major first-
pass hepatic
metabolism)
Route of elimination Active
Metabolites
Drug
accumulation
in renal
disease
Atenolol 6-9 No Renal Excretion (RE) No Yes
Metoprolol 3-7 Yes Hepatic Metabolism (HM) No No
Bisoprolol 10-12 No RE (≈50% unchanged) and
HM
No Yes
Carvedilol 6-10 Yes HM/biliary Yes No
Propranolol 3-10* Yes Hepatic Metabolism (HM) Yes No
*-for Long acting upto 10 hrs for short acting-3-4 hrs

18. So, in this patient, metoprolol succinate formulation can be initiated….since,
 Once daily administration (Better compliance)
 24 hour duration of action
 Therapeutic plasma concentration is smooth and uniform throughout
24 hours
 Higher beta-1-selectivity and less side effects
 Higher degree of response among hypertensive patients(Better
tolerability)

19. 19
Coming back to this case
 This patient is suitable for initiating beta blocker therapy preferably
Metoprolol with gradual increment of tolerated doses along with other
medications.
 To have optimum efficacy, go for original beta blocker.

20. Let’s look at the need to intensify Statin therapy in this patient
Beta-blocker Statin

21. Back to this case…
Patient profiles in terms of therapeutic intervention for Dyslipidemia –ESC 2019
LDLc Target
<116 mg/dl
Low CV Risk
LDLc Target <100
mg/dl
LDLc Target
<70 mg/dl
LDLc Target
<55 mg/dl
Moderate
CV Risk
High CV Risk Very High CV Risk
Young patient <10
years duration of
Diabetes Mellitus
 T1DM <35 yr
 T2DM <50 Yr
• TC >310 mg/dl)
• LDL c >190 mg/dl
• BP >180/110
• Family History without
other risk factor
• Moderate renal function
(30-59 ml/min)
• >10 years Diabetes
Mellitus without target
organ damage or other
additional risk factor
 ASCVD (Clinical /
Imaging)
 Family History of ASCVD
or with another major
risk factor
 Severe renal failure
patient (<30 eGFR)
 DM with target organ
damage with >3 risk
factors
 >20 years of T1DM
European Heart Journal, Volume 41, Issue 1, 1
January 2020, Pages 111–188
• Need to intensify the dose of
statin

23. ESC 2019 guideline on dyslipidemia management
European Heart Journal, Volume 41, Issue 1, 1
January 2020, Pages 111–188

24. Hypertriglyceridemia treatment for this patient-
as per ESC-2019
European Heart Journal, Volume 41, Issue 1, 1
January 2020, Pages 111–188
 Need to intensify the dose of statin, no need to initiate anything
else than statin

25. Rosuvastatin was found to be more effective in reducing LDL-C, LDL/HDL ratio and Non HDL C vs Atorvastatin at 16 weeks (ITT
population) – URANUS Trial
• Christian Berne et al; URANUS Study; Cardiovascular Diabetology 2005, 4:7
p < 0.0001 p < 0.0001 p < 0.0001NS NS
Doses were titrated from week 4 to week 16 in patients who had not reached the 1998 European LDL-C goal (<
3.0 mmol/L) (<115 mg/dl)
ITT: Intention to treat, CI: Confidence interval, LDL-C: Low-density lipoprotein cholesterol, TC: Total cholesterol, HDL-C: High-density lipoprotein
cholesterol, TG: Triglycerides, NS: Not statistically significant
-52.3%
5.3%
-21.2%
-54.1%
-45.0%
-45.5%
4.0%
-21.1%
-47.0%
-39.6%
LDL -C HDL-C TG LDL -C/HDL
RATIO
NON HDL C
Rosuvastatin 10-40 mg Atorvastatin 10-80 mg
 Patients aged ≥ 18
years
 Type 2 diabetes
 LDL-C ≥ 127.6 mg/dl

26. Percentage of patients achieving LDL-C goals at 4 weeks are
higher with Rosuvastatin 10mg- URANUS Trial
• Christian Berne et al; URANUS Study; Cardiovascular Diabetology 2005, 4:7
81%
65%
65%
33%
L D L - C < 1 1 5 M G / D L L D L - C < 1 0 0 M G / D L
Rosuvastatin Atorvastatin
*p < 0.001
*p < 0.001
LDL-C: Low-density lipoprotein cholesterol
 Patients aged ≥ 18
years
 Type 2 diabetes
 LDL-C ≥ 127.6 mg/dl

27. 27
Coming back to this case
 This patient is suitable for moderate intensity statin therapy.
 Keeping LDL c goal <70 mg/dl, moderate to high dose of statin has to
initiate.
 To control LDL c, Rosuvastatin is more effective than Atorvastatin in diabetic
dyslipidemia patient.
 For TG control, Mono statin is recommended as first drug of choice,
Rosuvastatin has shown good TG control in Diabetic Dyslipidemia patients.
 To have optimum efficacy, go for original statin.

28. THANK YOU