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Hypertension
Figure 2: Effect of Fixed Dose Combination American and European HTN guidelines have integrated the use of
versus Free Drug Combination on the Risk of
single-pill combinations into their therapeutic schemes.
Non-compliance to Medication Regimens
30
Single-pill Combinations and Therapeutic Efficacy
Overall
One important rationale for using single-pill combinations as first-
Study Risk Ratio Weight (%)
line therapies is to improve efficacy. There is no doubt that combination
Dezzi et al., 2000
a
0.74 (0.65, 0.84) 17.5
therapy is more effective lowering BP than monotherapy and that the
Dezzi et al., 2000
a
0.71 (0.62, 0.80) 17.6
likelihood of controlling BP is greater when starting with a single-pill
Eron et al., 2000
b
0.78 (0.55, 1.11) 4.3
combination. Whether a single-pill combination has superior
Geiter et al., 1987
c
0.88 (0.55, 1.42) 2.5
antihypertensive efficacy to the same drugs taken separately is another
Melikian et al., 2002
d
0.50 (0.35, 0.71) 4.2
question. Theoretically, there should be no difference between the two
Melikian et al., 2002
d
0.47 (0.22, 1.01) 1
strategies because the same drugs are prescribed. Thus, at comparable
NDC Dataset, 2003 0.81 (0.77, 0.86) 29
compliance, the single-pill combination should be equivalent to the two-
Su et al., 2002
e
0.89 (0.51, 1.57) 1.8
drug treatment. Interestingly, studies have not really supported this
Taylor et al., 2003
f
0.74 (0.67, 0.81) 22.1
assumption as single-pill combinations have regularly been found to be
Overall 0.74 (0.69, 0.80) 100
more effective than the same drugs taken separately. This was
0.1 1.0 10.0
confirmed in a meta-analysis of 354 randomised, double-blind, placebo-
Risk ratio
Favours fixed dose Favours free drug
controlled trials of five different categories of antihypertensive therapy.
24
combinations combinations In this analysis, the reduction in BP with drug combinations was additive,
Heterogeneity chi
2
= 14.49 (p=0.07) Egger’s publication bias (p=0.43) with combinations of two or three drugs at half standard dose being
Vertical solid line = null effect; vertical dotted line = overall effect on compliance; boxes and
preferable to one or two drugs at standard dose. In a recent Canadian
horizontal lines = relative risk (95% confidence interval). randomised, controlled study, investigators compared a simplified
a. Dezii, Manag Care, 2000;9(s):S7–S12; b. Eron et al., AIDS, 2000;14:671–81; c. Geiter et al.,
Tubercle, 1987;68(2 Suppl):41–6; d. Melikian et al, Clin Ther, 2002;24:460–467; e. Su and Perng, Int
algorithm for the treatment of HTN based on the initial use of a single-
J Tuberc Lung Dis, 2002;6:1029–32; f. Taylor and Shoheiber, Congest Heart Fail, 2003;9:324–32. pill combination of a diuretic and a renin–angiotensin system blocker
with the conventional guideline-based care recommending a step-care
Taken together, the problems associated with lack of achievement of approach.
25
The initial use of single-pill combinations was associated
BP goals are clearly multifactorial and interrelated. Patient compliance with a significantly higher proportion of patients achieving the target BP
with the treatment and physician compliance with the guidelines are (64.7 versus 52.7%). These results tend to confirm the superiority of
both related to the convenience and simplicity of the regimen, as well single-pill combinations over individual therapies. Of note, in the
as to the efficacy and safety of the antihypertensives prescribed. It Avoiding CV Events through CoMbination therapy in Patients LIving with
seems obvious that if the efficacy and safety of the treatment regimen Systolic HTN (ACCOMPLISH) trial, the use of single-pill dual combinations
could be improved alongside improvements in simplicity designed to led to a high percentage of well-controlled patients (>70%), regardless of
increase compliance, BP targets may be more easily attained. Perhaps the combination used (angiotensin-converting enzyme [ACE]–diuretic or
an ideal treatment regimen would be a single pill that could effectively ACE–calcium-channel blocker [CCB]).
26
Of course, this study was not
and efficiently reduce BP over a 24-hour period, cause minimal adverse designed to test the superiority of a single-pill combination over
effects – particularly metabolic side effects – and be cost-effective. individual drugs; nevertheless, it demonstrates the potential of single-pill
combinations to achieve a high percentage of adequate BP control
Single-pill Combination Therapies – including in patients with high cardiovascular risk.
A Solution to Improve Blood
Pressure Control? Single-pill Combinations and Drug Adherence
In recent years, there has been a progressive shift from the classic step- One of the major reasons why single-pill combinations may provide
care approach to the use of single-pill combinations as first-line greater benefits in terms of BP control is certainly linked to drug
therapy.
23
This change in paradigm has resulted from evidence that the adherence. Drug adherence is known to decrease in proportion to the
majority of patients included in large clinical trials require at least two frequency of the dose regimen with an almost 35% lower adherence in
antihypertensive agents acting on different mechanisms to achieve the a four-times-a-day regimen versus a once-a-day prescription.
27
Single-
pre-defined target BP. There are several good reasons why multiple- pill combinations are likely to increase compliance and persistence
mechanism therapies have greater efficacy in controlling BP in because they simplify the treatment regimen and reduce the pill
hypertensive patients. The first is that the likelihood of normalising BP is burden. Data are now accumulating that substantiate this hypothesis. In
higher if one attacks more than one BP-control pathway. In addition, a retrospective US database analysis comparing adherence and
when combining therapeutic strategies, each component has the medical resource use of patients (n=2,754) receiving a single-pill
potential to neutralise counter-regulatory mechanisms and the combination of amlodipine desylate and benazepril hydrochloric acid
additional BP reductions that often result. The best example of such a (HCl) with that of patients (n=2,978) receiving an ACE inhibitor and a
synergism is the association of a renin–angiotensin system blocker and long-acting dihydropyridine CCB as separate drugs, one-year
a thiazide diuretic. Moreover, with combination treatment both agents persistence on therapy was better in patients receiving the single-pill
can often be given at lower doses than either one alone, which can combination.
28
This observation is supported by several other
translate into an improved tolerability profile.
24
publications indicating significantly greater adherence in terms of pill
possession or persistence among patients receiving a single-pill
Single-pill combination therapies can offer all the advantages of a combination compared with separate two-pill regimens. Thus, patients
multiple-mechanism therapeutic strategy while potentially improving were twice as likely to be non-adherent with two pills compared with a
drug adherence, tolerability and costs. For these reasons, both single-pill combination and nearly 1.5 times more likely to be non-
54 EUROPEAN CARDIOLOGY
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