PRACTICAL ISSUES AND UPDATES

Improve adherence to antihypertensive therapyby using fixed-dose combinations

Adis Medical Writers

Published online: 11 December 2012

� Springer International Publishing Switzerland 2012

Abstract Suboptimal blood pressure control is common,

with poor patient compliance contributing to its develop-

ment. Compliance may be improved by simplifying anti-

hypertensive treatment (e.g. by reducing the pill burden

through the use of fixed-dose combinations).

Suboptimal blood pressure control is common

The primary goal of treating hypertension is to reduce

blood pressure (BP) to the guideline-recommended target

of \140/90 mmHg (or \130/80 mmHg in patients with

diabetes mellitus and those with high cardiovascular risk),

thereby reducing the risk of cardiovascular events, mor-

bidity and death [1]. However, despite these targets and the

relationship between hypertension and the risk of cardio-

vascular events, suboptimal BP control is common, with

only 31–46 % of patients with hypertension in Europe

estimated to achieve adequate BP control [2], resulting in a

substantial health and economic burden [1].

Often due to poor patient compliance

According to the World Health Organization [3], over half

of the patients receiving antihypertensive therapy drop out

of care entirely within a year of diagnosis, with &50 % of

those remaining under medical supervision taking at least

80 % of their prescribed medication. Low levels of patient

compliance are a major contributor to the development of

suboptimal BP control [1]. In addition, low adherence

(\80 %) to antihypertensive therapy correlates with a

higher risk of vascular events, whereas high (C80 %)

adherence is associated with significant reductions in car-

diovascular and cerebrovascular outcomes. Compliance

with antihypertensive therapy is therefore critical for

effective management of BP goals [1].

This article summarizes a review by Erdine [1] on the

effect of compliance, convenience and tolerability on BP

pressure control.

Multiple factors affect compliance

Compliance is affected by multiple factors (Table 1) [1].

Some factors, such as the complexity of the treatment

regimen, are of particular importance to patients who have

co-morbid conditions and who are receiving multiple

medications. Compliance may be improved in a number of

ways, including encouraging patients to become more

accountable for their own health; improving patient edu-

cation; raising awareness of the dangers of hypertension;

and treatment simplification [1].

Consider fixed-dose combination therapy…

As the majority of patients with hypertension require two

or more agents to achieve their BP targets, simplifying

treatment by reducing the pill burden (e.g. through the use

of fixed-dose combinations) is one of the most straight-

forward and effective ways of improving compliance [1].

Antihypertensive agents from different classes can be

combined if [4]:

Adis Medical Writers (&)

41 Centorian Drive, Private Bag 65901, Mairangi Bay,

North Shore 0754, Auckland, New Zealand

e-mail: DTP@adis.com

Drugs Ther Perspect (2013) 29:24–26

DOI 10.1007/s40267-012-0006-8

• they have different, albeit complementary, mechanisms

of action;

• there is evidence that the antihypertensive effect of the

combination is greater than that of either agent alone;

• the combination has a favourable tolerability profile,

with the complementary mechanisms of action mini-

mizing their individual adverse events.

…with two…According to a meta-analysis of 42 studies [5], com-

bining two agents with complementary mechanisms of

action was more effective in lowering BP than doubling the

dose of either agent alone. In addition, the incidence of

adverse events following the coadministration of two

antihypertensive agents was less than additive, and the risk

of cardiovascular events was reduced [6]. Dual combina-

tion therapies that have demonstrated efficacy and tolera-

bility in clinical studies include [4]:

• a b-blocker plus a dihydropyridine calcium channel

blocker (CCB);

• a CCB plus an angiotensin-converting enzyme (ACE)

inhibitor;

• a CCB plus an angiotensin receptor blocker (ARB);

• a CCB plus a thiazide diuretic;

• a thiazide diuretic plus an ACE inhibitor;

• a thiazide diuretic plus an ARB.

Unlike other antihypertensive drug classes, ACE inhib-

itors and ARBs do not exhibit dose-dependent increases in

the incidence of adverse events and, therefore, can be used

in combination therapy at higher doses than with agents

from other classes [1, 4]. Of note, ARBs have a more

favourable tolerability profile, with lower rates of cough

and angioedema, than ACE inhibitors [1].

A large-scale US survey found that fixed-dose combi-

nation therapy resulted in significantly higher compliance

and fewer all-cause hospitalizations and emergency room

visits than the administration of the same agents as separate

pills (free-drug combination therapy) [7]. The reductions in

medical costs with fixed-dose combination therapy more

than offset the higher drug costs within most US states [7].

In a recent meta-analysis, fixed-drug combination ther-

apy was associated with a significant improvement in the

compliance of patients with hypertension compared with

free-drug combination therapy [8]. However, no significant

between-group difference in systolic and diastolic BP were

observed [8].

…or more agents

Approximately one quarter (15–20 %) of patients with

hypertension will require therapy with at least three anti-

hypertensive agents in order to achieve BP control [1].

Current European guidelines recommend triple combina-

tion therapy comprising a renin-angiotensin system

blocker, a CCB and a thiazide diuretic as a rational treat-

ment strategy for these patients [9]. In two large

(n [ 2,000) randomized, double-blind, multicentre studies

in patients with moderate-to-severe hypertension, olme-

sartan/amlodipine/hydrochlorothiazide [10] and valsartan/

amlodipine/hydrochlorothiazide [11] were significantly

more effective than dual combination therapies of the

individual components in reducing and controlling BP. All

therapies were generally well tolerated.

Disclosure This article was adapted from the American Journal ofCardiovascular Drugs 2012;12(5):295–302 [1] by Adis editors and

medical writers. The preparation of this article was not supported by

any external funding; however, medical writing services for the ori-

ginal review [1] were funded by Daiichi Sankyo Europe GmbH.

References

1. Erdine S. How do compliance, convenience, and tolerability

affect blood pressure goal rates? Am J Cardiovasc Drugs. 2012;

12(5):295–302.

2. Wang YR, Alexander GC, Stafford RS. Outpatient hypertension

treatment, treatment intensification, and control in Western Eur-

ope and the United States. Arch Intern Med. 2007;167(2):141–7.

3. Adherence to long-term therapies: evidence for action. Geneva:

World Health Organization; 2003.

4. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines

for the management of arterial hypertension: the Task Force for

the Management of Arterial Hypertension of the European

Society of Hypertension (ESH) and of the European Society of

Cardiology (ESC). J Hypertens. 2007;25(6):1105–87.

5. Wald DS, Law M, Morris JK, et al. Combination therapy versus

monotherapy in reducing blood pressure: meta-analysis on 11,000

participants from 42 trials. Am J Med. 2009;122(3):290–300.

6. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering

drugs in the prevention of cardiovascular disease: meta-analysis

of 147 randomised trials in the context of expectations from

prospective epidemiological studies. BMJ. 2009;338:b1665.

7. Yang W, Chang J, Kahler KH, et al. Evaluation of compliance

and health care utilization in patients treated with single pill vs.

free combination antihypertensives. Curr Med Res Opin. 2010;

26(9):2065–76.

8. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and

effectiveness of fixed-dose combinations of antihypertensive

agents: a meta-analysis. Hypertension. 2010;55(2):399–407.

Table 1 Factors affecting compliance [1]

Asymptomatic nature of hypotension

Cognitive function

Concerns regarding adverse events

Concomitant diseases (e.g. depression)

Demographic factors (e.g. age)

Drug costs

Healthcare system-related issues

Knowledge of and attitudes towards hypertension and

cardiovascular risk

Quality of life

Treatment complexity

25

9. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of

European guidelines on hypertension management: a European

Society of Hypertension Task Force document. J Hypertens.

2009;27(11):2121–58.

10. Oparil S, Melino M, Lee J, et al. Triple therapy with olmesartan

medoxomil, amlodipine besylate, and hydrochlorothiazide in

adult patients with hypertension: the TRINITY multicenter,

randomized, double-blind, 12-week, parallel-group study. Clin

Ther. 2010;32(7):1252–69.

11. Calhoun DA, Lacourciere Y, Chiang YT, et al. Triple antihy-

pertensive therapy with amlodipine, valsartan, and hydrochloro-

thiazide: a randomized clinical trial. Hypertension. 2009;54(1):

32–9.

26