(Note: I was in the major vesnarinone trial and 
was taking the highest dose. It had no efect on 
me, and luckily - depending on who you ask - didn't
kill me :-)

The New England Journal of Medicine Vol. 339, No. 25
December 17, 1998

Inotropic Therapy for Heart Failure

	Heart failure treatment has changed since the
first large clinical trial of vesnarinone in April of 
1990. Then, heart failure was considered a defect that 
could be remedied by drugs which increased the heart's 
ability to contract or beat strongly (cardiac 
contractility).
	IV (intravenous) dopamine and dobutamine were 
widely used to increase cardiac output with less side 
effects than isoproterenol, epinephrine, and 
norepinephrine. Even though a higher risk of death 
(mortality) was found with long-term outpatient IV 
dobutamine use, and with oral pirbuterol and xamoterol,
there was hope that inotropic drugs acting in different
ways might do the trick.
	Phosphodiesterase inhibitors (amrinone, 
milrinone) increased heart contraction strength but 
small trials of amrinone raised concern about 
mortality, along with other serious side effects.
	Milrinone had fewer side effects but stopping 
its use after 2-10 weeks led to deterioration below the
level patients had before the drug trial (baseline). In
other words, the drug speeded up disease progression. 
From the small trials of these drugs, a trend was seen 
of higher mortality with long-term use.
	The Prospective Randomized Milrinone Survival 
Evaluation trial was started in 1989. Without improving 
symptoms, milrinone was associated with a mortality rate 
of 30%, compared to 24% with placebo over 6 months. The
trial was stopped early, in October 1990.
	As the vesnarinone trial proceeded (1990), the 
curtain also fell on 2 other inotropic drugs. Despite 
increasing exercise ability and quality of life,
pimobendan was also found to increase mortality.
Flosequinan improved functional capacity and was widely
prescribed, until increased mortality led to its 
withdrawal from the market.
	Reports of a survival benefit with vesnarinone
came as a surprise in 1993. The mortality rate was 62% 
lower with a daily dose of 60mg vesnarinone than with 
placebo. This was based on a 6 month trial with 33 deaths
in the placebo group and 13 in the vesnarinone group. It
might have been viewed differently if the analysis 
included the 16 deaths among patients taking 120mg of 
vesnarinone. That dose had been discontinued earlier in
the trial.
	The FDA did not approve vesnarinone and 
another trial was designed to include placebo patients,
30mg vesnarinone per day patients and 60mg per day 
patients. After 232 deaths in the placebo group, the 
trial was stopped. Mortality was 23% in the patients 
given 60mg of vesnarinone, compared to 19% in the 
placebo group, a 21% increase in the risk of death for 
people taking vesnarinone.
	CHF is seen as a disease of heart remodeling.
Current therapy includes ACE inhibitors to slow the 
disease and lower mortality, as well as to improve
symptoms. Loop diuretics relieve fluid retention. 
The importance of diuretics for advanced CHF is shown
by the increase in mortality with severe congestion. 
For CHF patients, digoxin has no effect on mortality.
	To slow disease progression, beta-blockers are
recommended for stable CHF patients not currently in 
Class 4 failure. Unstable or Class 4 patients require 
careful individualized therapy, which can include ACE 
inhibitors, nitrates, hydralazine, ACE 2 drugs and 
additional diuretics such as spironolactone. A critical
part of CHF management is enrolling patients in a 
program of education, counseling about physical 
activity and regular telephone contact.
	For patients who respond to standard drug therapy, 
there is now no role for inotropic drugs but therapy 
cannot be the same for all CHF patients. With beta-
blockers, patients are often willing to endure an initial
increase in symptoms like fatigue or shortness of breath
in the hope of a survival benefit down the road.
	Despite ACE inhibitors and beta-blockers, CHF 
remains a progressive disease and there are 50,000 to 
200,000 patients for whom even the best medical therapy 
cannot provide relief. For many of them, survival is not
a goal unless it is accompanied by some symptom relief.
Therapies that improve symptoms, even without improving
survival, attract patients.

	Are we ready to consider therapies that offer 
symptom relief at the price of a sooner death? Many 
doctors seem ready to give such therapies. Some promote
giving outpatient infusions of inotropic drugs. The 
only controlled data suggest that this increases risk of
death. Zeal for new CHF therapies also led to extensive
surgical removal of heart tissue (ventriculectomy or the
Batista Procedure), leading to a frequent need for 
salvage therapy and unpredictable improvement among 
survivors.
	Some patients may be ready to trade a greater 
risk of death for a chance to feel better. Even with only
Class 2-3 symptoms (shortness of breath with moderate 
exertion), 40% of patients expressed willingness to 
accept a 5% risk of death in order to gain a 5-point 
improvement in the 105-point score of the Living with 
Heart Failure questionnaire.
	Patients hospitalized while awaiting transplant
said they were willing to take a 50% risk of death for
a chance at better health. In those with Class 3-4 CHF,
49% were willing to trade at least half of their 
remaining time alive in order to feel well.
	The current vesnarinone trial provides 
information about relief of symptoms. In contrast to 
milrinone, vesnarinone did not increase hospitalizations 
for CHF and the excess deaths were sudden (which might 
be changed by ICD use). Vesnarinone seems to have a 
better benefit to risk ratio in patients with the most
severe heart failure. They are most willing to trade 
survival time for quality of life.
	A "population's" risk of sudden death may not
outweigh relief of symptoms for an individual patient.
There is also no indication of what value patients would
place on an improvement in their quality of life that 
peaked at 4 months, and went downhill after that, as seen
in the current vesnarinone trial.
	Clinical trials do not accurately reflect 
clinical practice. The study drug and background therapy
are kept constant in a trial but in actual practice, the 
doctor and patient adjust therapies by trial and error. 
Treatments that coincide with improvement are continued;
others are often stopped, especially if they carry 
substantial risk.
	What would be the effect on symptoms and survival 
if a drug such as vesnarinone were continued only when 
symptoms improved? Would the risk of an adverse outcome be 
reduced? How long should we wait for a response? Could 
therapy be discontinued safely in patients without a 
response? 
	Looking back, it has been clear for some time that
inotropic therapy does not have a role in the treatment of
most heart failure patients. Looking forward, however, 
there may be a place for drugs that cause enough symptom
relief to justify an increased risk of death for some 
patients. This group should include only those in whom 
the best available therapies have failed, a population of 
perhaps 100,000 patients out of the more than 4,000,000 CHF
patients in the USA today.

Lynne Warner Stevenson, MD.
Harvard Medical School
Boston, Massachusetts