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Newer antihypertensive combinations

An article from the e-journal of the ESC Council for Cardiology Practice

Hypertension is no longer seen as being part of a continuum of cardiovascular risk and historical targets of optimal blood pressure control; indeed the concept is more now of aggressive multiple risk factor reduction than treating risk factors in isolation.

Hypertension


This has led to the need for multiple drugs and aggressive management, which in turn call for the use of more multi-drug combinations. Certain combinations are logical, easy to initiate and help to achieve optimal protection better that the use of single agents.  

A targeted risk reduction approach

We have known for a long time that hypertension is dangerous and that treatment is effective.
More recently we have appreciated that even mildly elevated or high normal pressures are associated with increased risk, and that multiple risk factors interact to worsen prognosis.

A direct corollary of this is that we should now be taking a targeted risk reduction approach, treating for example, blood pressure to lower levels in higher risk subjects such as diabetics. ACE inhibitors are now used in high risk people with normal blood pressures, lipid lowering agents in patients with normal blood lipid levels and both together in diabetics.

The targeted risk reduction approach has also led some to question the usefulness of our linear thinking on the use of drugs, commencing them one by one and often never reaching the desired treatment outcome as a result.
Patients do not like taking multiple tablets and doctors do not like having to prescribe extra drugs and both these facts subconsciously conspire to avoid the full necessary treatment.
New combination preparations give us opportunities and strategies for achieving much more substantial risk reduction, and more effective protection for our patients.

The need for combination tablets

The Hypertension Optimal Treatment (HOT) Trial showed us the value of achieving lower BP targets.

What it also demonstrated was that to achieve these levels 3 or 4 separate blood pressure medications were frequently needed. Combining effective therapies in a single pill simplifies the regime and speeds up the process of gaining control. 

Recent surveys show that as few as 1/3rd of hypertensive patients (and 1/10th of diabetics) are treated to goal. If we can make logical, easy to use combinations we would materially enhance the chance of reaching target, by reducing the number of steps needed to get there.
Certain combinations are more logical; either because the component elements augment each other’s effects or antagonise each other’s side-effects.

Combinations in the 4 major BP lowering groups : ABCD

The 4 major BP lowering groups can be summarised by the acronym ABCD standing for ACE inhibitors (or angiotensin receptor antagonists) A, beta-blockers B, calcium channel blockers C, and diuretics D.

Logical combinations are A with D and B with C, with ACD being an attractive option for triple therapy. The AD combination was the basis of the LIFE  trial, which proved to be superior to a BD combination of atenolol with a thiaside.

Many commercial tablets combine an ACE inhibitor or an angiotensin receptor antagonist with a low dose thiazide and beta blocker/calcium channel blockers have been around for many years.

More recent combinations

More recent are combinations such as Trandolapril with Verapamil (Tarka) which have been studied recently. In the Invest study the predominant use of verapamil with trandolapril and hydrochlorthiazide was as effective as atenolol with trandolapril and hydrochlorthiazide in protecting against major cardiovascular events.

Other recent combinations include ACE inhibitor/CCB combinations.
In most studies the combinations have been shown to be effective in situations where monotherapy with the components is not, and in some cases (most notably AD combinations) more effective than the added effect of the two would be expected to achieve.
Another approach is to combine elements that reduce cardiovascular risk from different approaches such as the combination of a lipid-lowering agent with an antihypertensive.
This may also increase compliance and with the results of the recent ASCOT-LLA trial substantially reduce risk.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

References


1 - Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998 Jun 13;351(9118):1755-62.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9635947&query_hl=2

2 - Brown MJ, Cruickshank JK, Dominiczak AF, MacGregor GA, Poulter NR, Russell GI, Thom S, Williams B; Executive Committee, British Hypertension Society. Better blood pressure control: how to combine drugs. J Hum Hypertens. 2003 Feb;17(2):81-6. Review.
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3 - Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002 Mar 23;359(9311):995-1003.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11937178&query_hl=6

4 -  Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, Erdine S, Bristol HA, Kolb HR, Bakris GL, Cohen JD, Parmley WW; INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003 Dec 3;290(21):2805-16.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14657064&query_hl=8

5 - Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003 Apr 5;361(9364):1149-58.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12686036&query_hl=10

VolumeNumber:

Vol4 N°01

Notes to editor


Andrew J.S. Coats, MA, DM, DSc, FRACP, FRCP, FESC, FACC, FAHA, FCSANZ, MBA
Dean, Faculty of Medicine
University of Sydney,
NSW, 2006, Australia 

Tel: +61-23515476
 Fax: +61-23516645
 e-mail: ajscoats@aol,com

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.