Medicines Q&As
Q&A 297.2
What is the rationale and evidence for combining angiotensin
converting enzyme inhibitors with angiotensin II receptor
antagonists in vascular diseases and hypertension?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Published: May 2012
Background
This Q&A is the third of a series of three Q&As on the rationale and evidence for combining
angiotensin converting enzyme inhibitors with angiotensin II receptor antagonist.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have
similar clinical effects but differ in their pharmacology: ACE inhibitors block the conversion of
angiotensin I to angiotensin II and prevent the breakdown of bradykinin whilst ARBs selectively
block the AT1 receptor (1). Excessive amounts of angiotension II leads to vasoconstriction and
increased aldosterone secretion causing further sodium and water retention, while bradykinin,
acting on receptors in the vascular endothelium, promotes release of vasodilators including nitric
oxide (2). The pharmacology of ACE inhibitors and ARBs is represented in Figure 1.
Figure 1: Interaction of ACE inhibitors and ARBs with renin-angiotensin system (RAS) (1).
An ACE inhibitor alone may not fully block the renin-angiotensin system. The continued production
of angiotensin II is incompletely understood but may be associated with alternate synthesis
pathways (see fig 1) (1). Therefore by utilising the combination of an ACE inhibitor and an ARB
you would expect to gain a more complete blockade of the renin-angiotensin system. The question
is: in practice does this translate into an improved clinical outcome for the patient?
From the NHS Evidence website www.evidence.nhs.uk
Medicines Q&As
Answer
High risk for Vascular Disease
The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial
(ONTARGET) (n= 25,620) looked at whether the combination of telmisartan and ramipril was
superior to ramipril alone as a treatment to prevent vascular events in high risk patients who had
cardiovascular disease or diabetes mellitus but did not have heart failure (3). The study also
evaluated whether telmisartan was non inferior to ramipril for the same indication. Patients were
randomised to receive either 80mg telmisartan (n=8542) or 5mg ramipril (titrated up to 10mg)
(n=8576) or a combination of the two drugs (n= 8502). The median follow up period was 56
months. The primary composite outcome was death from cardiovascular causes, myocardial
infarction, stroke or hospitalisation for heart failure. In the combination therapy group the primary
outcome occurred in 1386 patients (16.3%; relative risk 0.99; 95% CI 0.92-1.07) as compared to
1412 patients in the ramipril group (16.5%). The main secondary outcome, composite of death
from cardiovascular causes, myocardial infarction or stroke, was the same in the combination
group and in the ramipril group (14.1%). Discontinuations due to hypotensive symptoms were
higher in the combination group (4.8%) than the ramipril group (1.7%). Renal dysfunction was
higher in the combination therapy group (13.5%) compared to the ramipril group (10.2%,
(p<0.001). The combination therapy was not found to be significantly better than either
monotherapy used and was associated with a higher number of discontinuations and adverse
effects. The study concluded that the combination of the two drugs in this group of patients did not
offer any additional clinical benefits.
Post Myocardial Infarction
The benefit of treatment with the combination of an ACE inhibitor and an ARB was not confirmed
in the only published trial carried out in post-myocardial infarction (MI) patients. The Valsartan in
Acute Myocardial Infarction (VALIANT) trial (n=14,703) included patients who had myocardial
infarction (0.5 to 10 days previously) complicated by left ventricular systolic dysfunction, heart
failure, or both and were randomised to receive valsartan (n=4909), valsartan plus captopril
(n=4885) or captopril (4909) which was titrated to target doses and adjusted according to patients
clinical status (4). The proportion of patients taking target doses were 56% for valsartan (160mg
twice daily), 47% for valsartan and captopril (80mg twice daily and 50mg three times daily
respectively), and 56% for valsartan (50mg three times daily) treatment. Mortality from any cause,
the primary outcome, was similar in the three treatment groups; 19.9% in the valsartan group,
19.3% in the combination group and 19.5% in the captopril group. The hazard ratio for the
combination group compared to captopril group was 0.98 (97.5% CI 0.89-1.09, P=0.73). A hazard
ratio was not given for mortality in the valsartan group vs. combined group as the study was not
designed for this comparison. The rate of the secondary end point of death from cardiovascular
causes, recurrent myocardial infarction, or hospitalisation for heart failure was also similar in the
three groups. Rates of hospitalisation for heart failure and myocardial infarction were numerically
lower in the combination group: 17.1% in the combination group, 18.7% in the valsartan group,
and 19.3% in the captopril group, the difference was statistically significant (p=0.007) between the
combination and captopril group. The study concluded that combination treatment did not reduce
mortality or cardiac outcomes. The highest rate of adverse events occurred in the combination
treatment group (9%) and the lowest in the valsartan group (5.8%).
Hypertension
The current guidelines from NICE and the British Hypertension Society do not recommend the
combination of an ACEI inhibitor and an ARB in the management of hypertension (5,6). A few
small trials have demonstrated that using this combination is more effective at reducing blood
pressure than monotherapy (7,8). A meta-analysis of 14 small RCTs involving 434 patients
compared the combination of ACE inhibitors and ARBs with either an ACE inhibitor or ARB alone
in the treatment of hypertension. The combination of an ACE inhibitor with an ARB reduced 24hour ambulatory blood pressure by 4.7/3.0 mmHg (95% CI, 2.9 to 6.5/1.6 to 4.3) when compared
with ACE monotherapy and by 3.8/2.9mmHg (95% CI, 2.4 to 5.3/0.4 to 5.4) when compared to
ARB monotherapy. Similarly, the combination reduced clinical blood pressure (sitting or supine) by
3.8/2.7 mmHg (95% CI, 0.9 to 6.7/0.8 to 4.6) and 3.7/2.3mmHg (95% CI, 0.4 to 6.9/0.2 to 4.4)
From the NHS Evidence website www.evidence.nhs.uk
Medicines Q&As
when compared with an ACE inhibitor and ARB respectively. However many of the trials used suboptimal doses or once daily doses of short acting ACE inhibitors and when larger doses or long
acting ACE inhibitors were used, there was generally no additive effect on blood pressure when an
ARB was added (9).
Long term effects over 12 months of dual blockade therapy on blood pressure were examined in
the CALM II study (n=75) where hypertensive type 1 and 2 diabetic patients received 16mg
candesartan and 20mg lisinopril (n=38) or high-dose 40mg lisinopril (n=37) (10). Dual blockade
treatment tended to be more effective than lisinopril monotherapy in lowering 24-hour and night
systolic blood pressure although the difference was not statistically significant. No difference in the
effect on diastolic BP was observed between the two treatment groups. A total of 15 patients (8
lisinipril and 7 dual blockade) had to be treated with thiazide diuretics due to insufficient blood
pressure reduction. Both treatments were generally well tolerated and no serious drug related
events were noted. The study concluded that reduction in blood pressure for dual therapy was
similar to dosage up-titration with the ACE inhibitor.
The largest study identified is the ONTARGET study (see ‘High risk for Vascular Disease’ section).
Blood pressure monitoring throughout the study showed that average blood pressure reductions
were lower in both the telmisartan group (a 0.9/0.6mmHg average reduction) and the combination
group (a 2.4/1.4mmHg average reduction) compared to the ramipril group although the statistical
significance of these results were not discussed. Overall effect of the combination, as discussed
earlier, did not offer any additional clinical benefit (3).
No studies have yet been carried out to demonstrate whether using this combination is as effective
in lowering blood pressure as combining an ACE inhibitor with another antihypertensive agent
such as a diuretic (8). Currently there appears to be no benefit in using the combination in mildmoderate hypertension. Most patients will achieve their target blood pressure using either agent as
monotherapy or by combining either agent with a diuretic. The data is less conclusive with respect
to severe hypertension in patients with diabetes and renal disease (11).
Summary
To date there is no convincing evidence to support the use of an ACE inhibitor in combination with
an ARB in patients with vascular diseases such as cardiovascular disease or diabetes mellitus
(high risk vascular patients) and post MI patients. Similarly the available evidence indicates no
additional benefit of combining an ACE inhibitor with an ARB for patients with mild to moderate
hypertension.
Limitations
Many of the studies looking at combination ACE inhibitor and ARB therapy for hypertension are
small and of short duration. For the other indications discussed in this Q&A; high risk for vascular
disease and post MI, only one study for each was identified indicating research in these areas is
extremely limited. The duration of action of different ACE inhibitors and ARBs might influence the
effect of different combinations and hence extrapolating results to other combinations may not be
appropriate.
References
(1)
Chiaventone K, Ou N. Cardiovascular Update: The role of combination ACE inhibitors
and angiotensin II receptor blockers. Pharma Times 2004; Dec: 92.
(2)
Chapter 5: Ace Inhibitors, ARBs, and Aldosterone Antagonists in Opie LH, Gersh BJ.
Drugs for the Heart. 6th Edition. Philadelphia, Pennsylvania: Elsevier and Saunders,
2005.
(3)
The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for
vascular vents. The New England Journal of Medicine 2008; 358 (15): 1547-1559.
(4)
Pfeffer MA, McMurray JJV, Velazquez EJ et al. Valsartan, captopril, or both in
myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.
The New England Journal of Medicine 2003; 349 (20): 1893-1906.
From the NHS Evidence website www.evidence.nhs.uk
Medicines Q&As
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
Williams B, Poulter NR, Brown MJ et al. Guidelines for management of hypertension:
report of the fourth working party of the British Hypertension Society, 2004 – BHS IV.
Journal of Human Hypertension 2004; 18: 139-185.
NICE. Hypertension – clinical management of primary hypertension in adults. Clinical
Guideline 127. August 2011. Accessed via www.nice.org.uk on 16/05/2012.
Kon Koh K, Quon MJ, Lee Y et al. Additive beneficial cardiovascular and metabolic
effects of combination therapy with ramipril and candesartan in hypertensive patients.
European Heart Journal 2007; 28: 1440-1447.
van de Wal RMA, van Veldhuisen DJ, van Gilst WH et al. Addition of an angiotensin
receptor blocker to full dose ACE-inhibition: controversial or common sense? European
Heart Journal 2005; 26: 2361-2367.
Doulton TWR, He FJ, MacGregor GA. Systematic review of combined angiotensinconverting enzyme inhibition and angiotensin receptor blockade in hypertension.
Hypertension 2005; 45: 880-886.
Anderson NH, Poulsen PL, Knudsen ST et al. Long-term dual blockade with candesartan
and lisinopril in hypertensive patients with diabetes. Diabetes Care 2005; 28 (2): 273277.
Sica DA. The practical aspects of combination therapy with angiotensin receptor
blockers and angiotensin-converting enzyme inhibitors. Journal of the ReninAngiotensin-Aldosterone System 2002; 3 (2): 66-71.
Summary of Product Characteristics. Capoten Tablets 25mg & 50mg. E.R. Squibb &
Sons Limited. Accessed via http://emc.medicines.org.uk. Date of access: 27/3/2012.
Date of revision of the text: June 2010.
Summary of Product Characteristics. Vascace. Roche Products Limited. Accessed via
http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of revision of the text: July
2010.
Summary of Product Characteristics. Innovace Tablets. Merck Sharpe & Dohme Limited.
Accessed via http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of revision of
the text: January 2011.
Summary of Product Characteristics. Fosinopril Sodium 20mg Tablets. Actavis UK Ltd.
Accessed via http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of revision of
the text: 12/8/2009.
Summary of Product Characteristics. Tanatril 5, 10 & 20mg Tablets. Chiesi Limited.
Accessed via http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of revision of
the text: 15/05/2010.
Summary of Product Characteristics. Zestril 2.5mg, 5mg, 10mg, and 20mg tablets.
AstraZeneca UK Limited. Accessed via http://emc.medicines.org.uk. Date of access:
27/3/2012. Date of revision of the text: 02/03/2012.
Summary of Product Characteristics. Perdix 7.5mg film-coated tablets. UCB Pharma
Limited. Accessed via http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of
revision of the text: August 2010.
Summary of Product Characteristics. Coversyl Arginine. Servier Laboratories Limited.
Accessed via http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of revision of
the text: December 2009.
Summary of Product Characteristics. Accupro tablets 5mg, 10mg, 20mg & 40mg. Pfizer
Limited. Accessed via http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of
revision of the text: August 2011.
Summary of Product Characteristics. Tritace 5mg Tablets. Sanofi-Aventis. Accessed via
http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of revision of the text: 29th
August 2011.
Summary of Product Characteristics. Gopten. Abbott Healthcare Products Limited.
Accessed via http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of revision of
the text: 7th Feb 2012.
Summary of Product Characteristics. Amias Tablets. Takeda UK Ltd. Accessed via
http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of revision of the text:
January 2011.
From the NHS Evidence website www.evidence.nhs.uk
Medicines Q&As
(24)
(25)
(26)
(27)
(28)
(29)
Summary of Product Characteristics. Teveten 300mg Film-coated tablets. Abbott
Healthcare Products Limited. Accessed via http://emc.medicines.org.uk. Date of access:
27/3/2012. Date of revision of the text: 18/01/2012.
Summary of Product Characteristics. Aprovel Film-Coated Tablets. Sanofi-aventis
Bristol-Myers Squibb SNC. Accessed via http://emc.medicines.org.uk. Date of access:
27/3/2012. Date of revision of the text: 17th June 2011.
Summary of Product Characteristics. COZAAR 12.5mg, 25mg, 50mg and 100mg FilmCoated Tablets. Merck Sharp & Dohme Limited. Accessed via
http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of revision of the text:
September 2011.
Summary of Product Characteristics. OLMETEC film-coated tablets. Daiichi Sankyo UK
Limited. Accessed via http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of
revision of the text: 28th October 2009.
Summary of Product Characteristics. Micardis 20mg, 40mg and 80mg tablets.
Boehringer Ingelheim Limited. Accessed via http://emc.medicines.org.uk. Date of
access: 27/3/2012. Date of revision of the text: 11 May 2011.
Summary of Product Characteristics. Diovan 160mg capsules. Novartis Pharmaceuticals
UK Ltd. Accessed via http://emc.medicines.org.uk. Date of access: 27/3/2012. Date of
revision of the text: 21 March 2011.
Quality Assurance
Prepared by
Varinder Rai, London Medicines Information Service (Northwick Park Hospital)
Based on earlier work by Aya Mizukami and Helen Rowlandson, London Medicines Information
Service (Northwick Park Hospital)
Date Prepared
16th May 2012
Checked by
Alexandra Denby, London Medicines Information Service (Northwick Park Hospital)
Date of check
22nd May 2012
Search strategy
 Embase [*DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR/cb and *ANGIOTENSIN
RECEPTOR ANTAGONISTS/cb] and [CARDIOVASCULAR DISEASE/dt and HEART
INFARCTION/dt and *HYPERTENSION/dt]. Limit to: Human and English Language and
Publication Year 2009-Current.
 Medline DRUG THERAPY, COMBINATION/ and [*ANGIOTENSIN RECEPTOR
ANTAGONISTS/ or ANGIOTENSIN-CONVERTING ENZYME INHIBITORS/tu] and
[HYPERTENSION/ or *CARDIOVASCULAR DISEASES/dt]. Limit to: Human and English
Language and Publication Year 2009-Current.
 In-house database/ resources
 NeLM “ace inhibitors” and “angiotensin”
 Cochrane Library “ace inhibitors” and “angiotensin”
From the NHS Evidence website www.evidence.nhs.uk
Medicines Q&As
Appendix 1: UK licensed indications for ACE inhibitors and ARBs *Please refer to current
Summary of Product Characteristics (SPC), which can be accessed via
http://emc.medicines.org.uk for full dosing information.
ACE Inhibitors (trade
name)
Hypertension
Heart
failure
Captopril
(Capoten) (12)
Cilazapril
(Vascace) (13)
Enalapril
(Innovace) (14)






Fosinopril (15)


Imidapril (Tanatril)
(16)
Lisinopril (Zestril)
(17)
Moexipril (Perdix)
(18)
Perindopril
(Coversyl
Arginine) (19)
Quinapril
(Accupro) (20)
Ramipril (Tritace)
(21)
Trandolapril
(Gopten) (22)
Angiotensin II
receptor
antagonists
Candesartan
(Amias) (23)
Eprosartan
(Teveten) (24)
Irbesartan
(Aprovel) (25)
Losartan (Cozaar)
(26)
Olmesartan
(Olmetec) (27)
Telmisartan
(Micardis) (28)
Valsartan (Diovan)
(29)



Post MI
prophylaxis

Post MI
prophylaxis
with LV failure

Diabetic
nephropathy
(type 1)
Diabetic
nephropathy
(type 2)
Cardiovascular
disease, stroke
or peripheral
disease











Hypertension

Heart
failure





Post MI
prophylaxis
Post MI
prophylaxis
with LV failure



Diabetic
nephropathy
(type 1)
Diabetic
nephropathy
(type 2)
Cardiovascular
risk reduction














From the NHS Evidence website www.evidence.nhs.uk
6