Download `optimal medical therapy`? The case of chronic heart failure

CURRENT OPINION
European Heart Journal (2013) 34, 2792–2794
doi:10.1093/eurheartj/eht279
Should we revise our approach to ‘optimal medical
therapy’? The case of chronic heart failure
Luigi Tavazzi 1*, Aldo P. Maggioni 2, and Jeffrey S. Borer 3
1
Maria Cecilia Hospital - GVM Care and Research, Ettore Sansavini Health Science Foundation, Via Corriera 1, 48010 Cotignola (RA), Italy; 2European Society of Cardiology,
Observational Research Programme, European Heart House, Sophia Antipolis, France; and 3State University of New York Downstate Medical Center, Brooklyn and New York, NY, USA
Received 18 December 2012; revised 31 May 2013; accepted 26 June 2013; online publish-ahead-of-print 25 July 2013
The concept of ‘optimal medical therapy’ relies on recommendations
of current consensus-derived guidelines, most of which are supported by ‘level of evidence C’ (no scientific evidence).1 However,
guidelines recommendations for commonly employed cardiovascular drugs often are based on strong evidence (‘level A’).2 Generally,
such drugs are recommended at ‘target doses’ employed in the
trials on which their putative efficacy and regulatory approval are
based, and are considered ‘optimal medical therapy’. Information
about the effectiveness of other doses, lower, or higher, seldom is
available.
Current drug target doses are
inconsistent with the clinical
practice
Currently, reports of randomized controlled trials of new drugs in
chronic heart failure (CHF) as well as in other conditions must quantitatively define the use of guidelines-recommended ‘optimal medical
therapy’, usually as the proportion of patients who took these drugs,
regardless of dose. However, in contemporary registries in CHF, for
which therapy is particularly complex, large segments of the affected
population fail to receive the recommended drugs and substantially
less than half receive guidelines-based ‘target doses’. This is apparent
from the Table 1, in which doses of drugs for CHF actually employed,
from the 12-country 2010 European Survey of the European Society
of Cardiology3 are compared with ‘target doses’ of the same drugs
from contemporary (2008) published guidelines.4
The use of beta-blockers for CHF is an example. In a recent trial—
SHIFT—testing the effect of a pure heart rate slowing agent—ivabradine—against placebo in patients with CHF, maximized guidelinesrecommended background therapy was mandated, specifically for
beta-blockers, which also slow heart rate.5 In SHIFT, 89% of patients
received a beta-blocker but only one-fourth reached the ‘target
doses’, and only 56% achieved ≥50% of target. These results subsequently were echoed in CIBIS-ELD,6 which evaluated doses of
bisoprolol and carvedilol (beta-blockers commonly used in clinical
practice) achieved in elderly patients with CHF. The drugs were randomized and then force-titrated to ESC Guidelines targets. At least
50% of the target dose was achieved in only 55% of the patients.
Similar results were obtained in community studies7,8 consistent
with the data reported in Table 1. This huge ‘underdosing’ might be
related to physician inexperience, undesired effects, or patients
fears of them, multimorbidity and the attendant polypharmacy, limiting the uptitration which may have been done in the original trials
from which the targets were derived, (of note, in the landmark
trials many patients, ranging from 22 to 53%, could not reach the
protocol-defined beta-blocker target doses in spite of forcedtitration). Nonetheless, the target doses recommended in the
current guidelines are those predefined as targets in these remote
studies, perpetually repeated in guidelines as ‘optimal medical
therapy’ in spite of evidence of increasingly diverging clinical practice.2 In fact, if the recommended target doses are appropriate, we
might infer that most patients currently are treated inadequately.
Alternatively, we might wonder whether the range of doses currently
used in clinical practice represents patient needs and drug tolerability
in the current era.
Target dose or target effect?
If guidelines-recommended ‘target doses’ should be reconsidered,
how can we define therapeutic recommendations? Perhaps, for
drugs affecting easily detectable ‘biomarkers’ related to their pharmacological effects and associated with proved clinical benefit and
safety, the concept of ‘target dose’ should be replaced by ‘target
effect’. This would imply that once the clinical benefit of a drug is
established, a strict and predictable relationship between drug efficacy and safety should be sought relative to an appropriate biomarker, if such exists. Thereafter, the biomarker response could guide
dosing. Early drug development often provides a basis for this
effort: new drugs commonly are tested in dose-finding studies
employing surrogate biomarker endpoints. However, such trials
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
*Corresponding author. Tel: +39 0545217564, Fax: +39 0545217327, Email: [email protected]; [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected]
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Should we revise our approach to ‘optimal medical therapy’?
Table 1 Rate of use and dosages of the most frequently prescribed renin– angiotensin– aldosterone system blockers
and beta-blockers. Modified from McMurray et al.2
Rate of use (%)
Dose (mg/o.d.)
median (IQR)
Target dose (%)
...............................................................................................................................................................................
Prescribed ACE-I and doses (n: 2078 )
Ramipril
Enalapril
50.1
27.8
5 (3.75– 10)
10 (10– 20)
38.2 (target dose 10 mg/die)
46.2 (target dose 20 mg/die)
Candesartan
Losartan
34.7
26.4
16 (8 –32)
50 (25– 50)
28.0 (target dose 32 mg/die)
19.7 (target dose 100 mg/die)
Valsartan
25.7
160 (80– 160)
16.7 (target dose 320 mg/die)
Prescribed ARBs and doses (n: 864)
Prescribed beta-blockers and doses (n: 2774)
Carvedilol
42.8
Bisoprolol
32.3
Metoprolol
18.9
Prescribed aldosterone antagonists and doses (n: 1396)
25 (12.5– 50)
5 (2.5–7.5)
100 (50– 150)
37.3 (target dose 50 mg/die)
20.7 (target dose 10 mg/die)
21.4 (target dose 200 mg/die)
Spironolactone
59.7
25 (25– 25)
22.2 (target dose 50 mg/die)
Canrenone
Eplerenone
27.3
10.5
50 (25– 50)
25 (25– 50)
61.3 (target dose 50 mg/die)
32.7 (target dose 50 mg/die)
are relatively small, commonly safety-oriented, and feature efficacy
endpoints frequently not practically transferable to clinical outcomes. The individual responsiveness to the drugs is variable;
lower doses may be better than higher as a function of patient
age, individual responsiveness, comorbidities, polypharmacy, etc.9
A biomarker could help in defining optimal dosing for individual
patients. Since many drugs used in prevention of major cardiovascular
events are intended for lifetime use, defining the lowest effective dose
for an individual may have important medical and socio-economical
implications. Professional Societies or Regulatory Bodies should
decide when a surrogate marker is acceptable to guide therapy and
which effect should be taken as the ‘target’.
Is this concept practically applicable? Indeed, it is applied systematically to titrate the drug doses in hypertension, diabetes, and dyslipidaemia.10 Besides the beta-blockers, discussed above, statins are
examples of drugs having a definable target effect related to outcomes. Actually both have many pharmacological effects (some
desirable, some not). We do not know the precise dose at which
the drug exerts each effect maximally, nor the relative contribution
of each pharmacological effect to the net clinical effect of the drug.
Thus, we do not truly know the ‘optimal dose’ for any individual
patient. However, for beta-blockers in CHF, we know the relationship between the drug-induced change in heart rate and some
important clinical outcomes. Hence, heart rate is a trustworthy
metric of the effect of beta-blockade, as recently shown by a wellconducted meta-analysis of randomized controlled trials11 and
other studies8 in CHF demonstrating that the dose of beta-blocker
has little influence on mortality while heart rate change induced by
the drug is directly associated with mortality benefit. Statins may be
the drug group in which the effects of individual approved drugs
differ most widely. Within this group, multiple doses of several
drugs have been compared head to head. The results have defined different doses of drugs that can achieve well-defined surrogate
biomarker outcomes (usually LDL cholesterol) which correlate
well with clinical benefit. LDL cholesterol is, indeed, a desirable
target biomarker since it is a modifiable risk factor (i.e. its change
relates directly to alteration in clinical outcomes), not just a risk
marker, of atherothrombosis. However, most statin trials employed
different fixed doses that were not modified according to the level of
LDL achieved.
A pragmatic biomarker-based approach to dosing has been applied
with several other groups of drugs, including anti-hypertensive,
antidiabetic, and anticoagulant agents. Indeed, several trials in hypertension and diabetes have shown the benefits of treating patients to
target blood pressures and HbA1c concentrations. The COURAGE
trial has set the standard for ‘optimal medical therapy’ by treating
patients effectively to multiple biomarker targets and averting
major adverse cardiac events,12 though the impact on clinical practice
has been less than expected.13
The principle of target effect cannot be applied for drugs with
primary effects not including suitable biomarkers. For instance, for
modulators of the renin–angiotensin–aldosterone system, blood
pressure might be the appropriate basis for dose selection for hypertension but not for heart failure. In patients with the latter condition
blood pressure could be monitored for safety, to prevent undesired
hypotension, but not for efficacy, which may be related to pharmacological effects other than on blood pressure. Antiplatelet agents have
been extensively investigated in search of the lowest dose that optimally balances antithrombotic and pro-haemorrhagic effects. However,
defining the best dose individually is difficult because of the lack of availability, to date, of a quick, reliable and inexpensive measure that can be
applied at the bedside.14 Ultimately, pharmacogenetics and perhaps
other and newer approaches will enable optimized individualized
dosing. Genetic variations associated with variations in responses to
drugs have been demonstrated for cardiovascular drugs including
diuretics, ACE inhibitors, and beta-blockers.15
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Observational data also can help to clarify drug and dose effects,
firstly by recording drug doses used in clinical practice. These may
result from beliefs and behaviours of physicians in prescribing drugs
or from beliefs of patients on their effectiveness and safety in taking
them. Secondly, long-term observational registries can be designed
to clarify the reasons why certain drugs are most commonly
employed at far lower than the guidelines-recommended targets.
Thirdly, these observational studies can assess data on drug effectiveness using analysis plans designed to minimize the (inevitable) uncertainty deriving from non-randomized studies
Finally, the writers of clinical practice guidelines (increasingly perceived as mandatory for all patients, with potential legal consequences
if they are abrogated) should consider the appropriateness of automatically confirming historically accepted standards, and should
take cognizance of the practical applicability of their guidelines, not
focusing only on the ,50% of affected patients able to reach the
standard target doses. It is important to recognize that, as each
new therapy is added to the existing list for any condition, we have
no information about the continuing benefit of therapies tested
before more current additions. In practice, the Guidelines should
discuss whether or not the drug doses defined in placebo-controlled
trials are still to be recommended in a new therapeutic context, and
the level of recommendations should be graduated accordingly.
Perhaps the presently recommended target doses might best be considered as thresholds beyond which drugs have not been tested,
rather than targets that must be achieved.
Authors’ contributions
L. Tavazzi et al.
3.
4.
5.
6.
7.
8.
9.
10.
L.T., A.P.M., and J.S.B. equally contributed to the preparation of
this text.
Conflict of interest: L.T. is consultant or committee member
for Boston Scientific, Cardiorentis, Servier, S. Jude Medical, Vifor
Pharma. A.P.M. is consultant or committee member for Novartis,
Cardiorentis, LonStar Heart, Servier, Amgen, Sanofi, Vifor Pharma.
J.B. is consultant or committee member for Astellas, Novartis, Celladon, Cardiorentis, Biotronik, Biomarin, Pfizer, Roche-Genentech,
Somahlution, Servier, and Salix.
11.
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