In a recent article, Komajda and colleagues (2005) presented data gathered from the
Medical Management of Chronic Heart Failure in Europe and its Related Costs (MAHLER)
survey in support of the view that adherence to guidelines in treating patients with
chronic heart failure is a strong predictor of fewer cardiovascular hospitalizations
in clinical practice.
Five types of drugs were considered as the agents of choice in the treatment of chronic
heart failure: angiotensin-converting enzyme (ACE) inhibitors, β-adrenoceptor antagonists
(blockers), potassium sparing diuretic (spironolactone), cardiac glycosides, and diuretics
other than the potassium-sparing class. The total number of patients included in the
trial were 1421, of whom 1333 (93.8%) completed the study. Baseline medications in
these patients were ACE inhibitors (69%), angiotensin type 1 receptor antagonists
(17.6%), β-adrenoceptor antagonists (53%), diuretics (79%), cardiac glycosides (41%),
and spironolactone (28%). Adherence was considered perfect if the first three (T3)
drugs (ACE inhibitor, β-adrenoceptor antagonist, and spironolactone) were used, and
this was compared with a situation when either the latter three were not used concomitantly
or a condition in which all five (T5) were used as part of the regime to treat chronic
heart failure. The overall guideline adherence indicators for T3 and T5 were 60% and
63%, respectively, with class adherence for ACE inhibitors (85.4%), diuretics (83%),
β-adrenoceptor antagonists (58%), cardiac glycosides (52%), and spironolactone (36%)
(Komajda et al 2005). Of particular interest, are two issues that are worth addressing
based on the findings from the Komajda et al report.
First, the data presented supports the view that β-adrenoceptor antagonists are underutilized
in the treatment of patients with chronic heart failure. This is somewhat surprising
as there is substantive evidence to indicate that this class of drugs should form
an integral part of a strategy in treating patients with this condition. A previous
survey on the quality of care among patients with heart failure in Europe had also
revealed an underutilization of β-adrenoceptor antagonists in these patients (The
Study Group of Diagnosis of the Working Group on Heart Failure of the European Society
of Cardiology 2003). The evidence from this report seems to indicate that the rate
of prescription for β-adrenoceptor antagonists was 36.9%, with metoprolol being the
most widely used (40.3%) agent among the β-adrenoceptor antagonists. There is clear
evidence from a number of clinical trials that indicate the benefits of β-adrenoceptor
antagonists in patients with left systolic dysfunction (Packer et al 1996, 2001; CIBIS-II
Investigation and Committee 1999; MERIT-HF Study Group 1999). As well, post-hoc analysis
of the data from Metoprolol Randomized Intervention Trial in Congestive Heart Failure
on many levels, ie, frequency of hospitalization, quality of life, and functional
class, indicate the clear beneficial effects of this class of drugs in treating patients
with chronic heart failure (Hjalmarson et al 2000; Goldstein et al 2001; Ghali et
al 2002; Gottlib et al 2002; Wikstrand et al 2002). The use of this class of drugs
reduces hospitalization due to worsening heart failure, increases life expectancy,
and reduces all-cause hospitalization (Tabrizchi 2003). Thus, perhaps a greater effort
should be made to encourage the appropriate use of this class of drugs in patients
with chronic heart failure.
Second, the trend was that the group of patients taking the three drugs, ie, ACE inhibitor,
β-adrenoceptor antagonist, and spironolactone (T3), were more likely to experience
hospitalization due to cardiovascular problems when compared with those taking the
five drugs (T5). This off-hand observation, if real, clearly needs closer examination.
Perhaps not surprisingly, a relatively simple hypothesis to explain this observation
would be on the basis of the pharmacological actions of the three agents employed.
The simple explanation would be an unwanted elevation of serum potassium levels resulting
in higher incidence of cardiovascular problems. It is interesting that following the
publication of the Randomized Aldactone Evaluation Study (RALES; The RALES Investigators
1996) there was an increase in the use of spironolactone. The concomitant use of spironolactone
and ACE inhibitors in patients with heart failure was stable in the period of early
1994 until early 1999 (∼34 per 1000 patients) (Juurlink et al 2004). However, subsequent
to the publication of RALES, the rate of prescription increased significantly (p <
0.001) by a factor of approximately fivefold (149 per 1000) by late 2001. Of interest
was the rate of hospital admission associated with hyperkalemia, which was 2.4 per
1000 in early 1994 and 4.0 per 1000 in early 1999, and that rate increased further
after the publication of RALES to 11.0 per 1000 (p < 0.001) by late 2001 (Juurlink
et al 2004). The use of ACE inhibitor and spironolactone together has the potential
to create a greater risk of the serum potassium becoming elevated in patients with
heart failure as does the use of a β-adrenoceptor antagonist (Swenson 1986; Hamad
et al 2001; Tamirisa et al 2004).
Therefore, it should not be a surprise that the combination of the three would provide
a clinical situation that could predispose the patient to a greater risk of manifesting
an elevated level of serum potassium. Moreover, one reason that the five drug combination
may not produce the same outcome is because of the fact that drugs such as thiazides
and loop diuretics cause some degree of serum potassium depletion by the virtue of
their pharmacological effects in the nephron. This action may prevent the rise in
serum potassium to levels that precipitate the cardiovascular problems exhibited by
the patients on the T3 drugs.
This hypothesis, of course, can easily be tested by examining electrolyte records
of patients on these drugs admitted for cardiovascular problems. However, more importantly,
the medical community must be made aware of the risk associated with this form of
drug interaction and implement appropriate guidelines to prevent its occurrence in
this patient population.