sure what to say.”
And the evidence is even scarcer when it comes
to devices for heart failure, said Dr. Jessup. Many of
the studies providing the foundation for the use of
implantable cardioverter-defibrillators (ICD) and cardiac resynchronization therapy (CRT) in HF did not
mention baseline renal function nor have they done
subgroup analyses according to renal function. “So
when we throw in an ICD for primary prevention in
a low ejection fraction patient with renal dysfunction, it is in an evidence-free zone,” she said.
The good news: where there is evidence available,
it appears that most of the drugs used to treat heart
failure offer benefits in patients with moderate (stage
3) renal dysfunction and actually appear to provide
added benefit compared to those with preserved
renal function. With greater renal insufficiency (CKD
stage 4 or 5), the data remain scarce.
“Although there is less robust evidence of benefit
in HF patients with a reduced GFR, subgroup analyses of the trials testing the major classes of drugs
(ACE-I, beta-blockers, mineralocorticoid receptor
antagonists, and angiotensin receptor blockers) and
devices (ICD/CRT) suggest that the relative risk
reductions are similar (and absolute risk reductions
greater), although these therapies might cause unwanted effects,” wrote Damman et al. in a review of
the evidence published last year.7 (See FIGURE 2.)
“Especially in patients with stage 4 and 5 CKD,
care should be taken to assess whether possible
beneficial effects might outweigh the potential risks
associated with the initiation of this therapy,” wrote
Damman et al.
No Trials = No Guidelines
How can the heart failure treatment guidelines
ignore half of the HF population? According to
Dr. McCullough, the problem starts with drug and
device development.
“These patients are excluded from clinical trials
because of the fact that they’re high risk and they
tend to be very complicated, and many of the manu-
“The guidelines—that have been so carefully crafted with our stage
A, B, C, and D, and our goals of therapy and treatments—[...] have
not paid much attention to the idea that there are patients with
renal dysfunction.” —Mariell Jessup, MD
facturers want to eliminate confounding and get a
clean look at their drugs,” he said.
Even worse, because many drugs have to be dose
adjusted for patients with renal dysfunction, the
agents really need to be properly studied rather than
just used in CKD patients because they’ve shown
safety and efficacy in non-CKD patients. Many
companies never really define drug dosing for renal
patients.
“To this day, we use heparin all the time and we
really don’t have accepted drug-dosing adjustments
for heparin, or enoxaparin as another example,
which is contraindicated below a certain level of
renal function,” said Dr. McCullough.
Exclusion from clinical guidelines is not surprising given that “one of the rules of guidelines is that
you need evidence, so if you don’t have evidence you
don’t get in the guidelines.” Now there is a Catch-22.
Several groups are now working with the National Institutes of Health and industry sponsors to have
kidney-disease pre-specified subgroups in the larger
clinical trials. The best example of this new era in
clinical trial research, stated Dr. McCullough, is the
National Heart, Lung, and Blood Institute-funded
ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive
Approaches). The main trial is testing the best
management strategy—invasive or conservative—for
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