Clinical Pharmacology and Therapeutics

DRUGS FOR HEART FAILURE 213
The drugs that are most effective in prolonging survival in
chronic heart failure work indirectly, by reducing preload,
afterload or heart rate, rather than directly by increasing the
force of contraction.
THERAPEUTIC OBJECTIVES AND GENERAL
MEASURES FOR CHRONIC HEART FAILURE
Therapeutic objectives in treating heart failure are
• to improve symptoms and
• to prolong survival.
General principles of treating heart failure:
• restrict dietary salt;
• if there is hyponatraemia, restrict fluid;
• review prescribed drugs and if possible withdraw drugs
that aggravate cardiac failure:
• some negative inotropes (e.g. verapamil)
• cardiac toxins (e.g. daunorubicin, ethanol, imatinib,
gefitinib, trastuzumab)
• drugs that cause salt retention (e.g. NSAID).
• consider anticoagulation on an individual basis.
DRUGS FOR HEART FAILURE
DIURETICS
For more information, see Chapter 28 for use of diuretics in
hypertension and Chapter 36, for mechanisms, adverse effects
and pharmacokinetics.
Use in heart failure
Chronic heart failure: a diuretic is used to control symptomatic
oedema and dyspnoea in patients with heart failure. A thiazide
(see Chapters 28 and 36) may be adequate in very mild cases,
but a loop diuretic (e.g. furosemide) is usually needed. Unlike
several of the drugs described below, there has been no randomized
controlled trial investigating the influence of loop
diuretics on survival in heart failure, but the other treatments
were added to a loop diuretic and this is usually the starting
point of drug treatment. Spironolactone improves survival in
patients with cardiac failure and counters diuretic-induced
hypokalaemia. Diuretic-induced hypokalaemia increases
the toxicity of digoxin. Conversely, spironolactone and other
K -retaining diuretics (e.g. amiloride, triamterene) can cause
severe hyperkalaemia, especially if given with ACEI or sartans
(see below) to patients with renal impairment. It is therefore
important to monitor plasma K during treatment with all
diuretic therapy.
Acute heart failure: acute pulmonary oedema is treated by sitting
the patient upright, administering oxygen (FiO 2 , 28–40%)
and intravenous furosemide which is often effective within a
matter of minutes. Intravenous morphine (Chapter 25) is also
useful. A slow intravenous infusion of furosemide by syringe
pump may be useful in resistant cases. Once the acute situation
has resolved the situation is re-assessed and drugs used for
chronic heart failure (see below), including oral diuretics, are
usually indicated.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
For the mechanism of action and other aspects of angiotensinconverting
enzyme inhibitors, see Chapter 28.
Use in heart failure
The first approach shown to reduce mortality in heart failure
was combined hydralazine and nitrate therapy (see below).
Soon after, an angiotensin-converting enzyme inhibitor (ACEI)
(captopril) was shown to do better. Other ACEI were also
shown to improve survival and ACEI treatment for heart failure
was rapidly adopted. When symptoms are mild, diuretics
can be temporarily discontinued a day or two before starting
an ACEI, reducing the likelihood of first-dose hypotension.
In these circumstances, treatment with an ACE inhibitor can be
started as an out-patient, as for hypertension (see Chapter 28).
A small starting dose is used and the first dose is taken last
thing before retiring at night, with advice to sit on the side of
the bed before standing if the patient needs to get up in the
night. The dose is gradually increased to one that improves
symptoms (and survival) with careful monitoring of blood
pressure. Serum potassium and creatinine are checked after
one to two weeks. Hypotension is more of a problem when
starting treatment in heart failure patients than when treating
hypertension, especially with short-acting drugs (e.g. captopril).
Not only is the blood pressure lower to start with, but
concentrations of circulating renin are high and increased further
by diuretics. ACEI cause ‘first-dose’ hypotension most
severely in patients with the greatest activation of the
renin–angiotensin system. These are consequently those most
likely to benefit from an ACEI in the long term. Long-acting
drugs (e.g. ramipril, trandolapril) cause less first-dose
hypotension and can be given once daily. ACEI are usually
well tolerated during chronic treatment, although dry cough
is common and occasionally unacceptable (see Chapter 28 for
other adverse effects). Important drug–drug interactions can
occur with NSAIDs (Chapter 26), which may cause renal
failure and severe hyperkalaemia, especially in heart failure
patients treated with ACEI.
ANGIOTENSIC RECEPTOR ANTAGONISTS, SARTANS
See Chapter 28 for the mechanism of action.
Use in heart failure
As in hypertension, the pharmacodynamics of sartans are similar
to those of ACEI apart from a lower incidence of some adverse
effects, including, particularly, dry cough. Several of these
drugs (e.g. candesartan, valsartan) have been shown to prolong
life in randomized controlled trials, the magnitude of the
effect being similar to ACEI. It is possible that they have some
additive effect when combined with ACEI, but this is hard to
prove at doses that are not supramaximal. Because of the
greater experience with ACEI and the lower cost, many physicians
prefer to use an ACEI, unless this is not tolerated.