Cases & Commentaries

One ACE Too Many

Commentary By David N. Juurlink, BPhm, MD, PhD

The Case

A 72-year-old man with coronary artery disease,
diabetes, and recently diagnosed congestive heart failure presented
to the emergency department (ED) with chest pain. An acute
myocardial infarction was ruled out. Because his admission
medication regimen did not include an angiotensin-converting enzyme
(ACE) inhibitor, one was started before discharge. He had no known
renal dysfunction. Two weeks later, he presented to the ED with
fatigue, lethargy, and a critically elevated serum potassium level.
Shortly thereafter, he suffered a cardiac arrest and died.

The patient had previously been receiving
outpatient care from an ancillary clinic of the hospital. When the
ED physician called to inform the clinic of the patient's death,
the primary care provider recalled that the patient previously had
been treated with an ACE inhibitor and had developed hyperkalemia
after 1 week of therapy. The ACE inhibitor had been discontinued at
that time.

The Commentary

This case illustrates how well-intentioned care
can sometimes have catastrophic consequences. It also highlights
how adherence to a few commonsense principles and the
implementation of integrated medical records could dramatically
lessen the risks of drug-related harm.

The incident described in the scenario resulted
from the physician's desire to provide timely, evidence-based care.
The patient had two apparent indications for an ACE inhibitor: type
2 diabetes and congestive heart failure. Unfortunately, both
conditions can predispose to hyperkalemia—diabetes because of
hyporeninemic hypoaldosteronism and congestive heart failure
because of impaired glomerular perfusion.(1-3)

Despite the good intentions, a few noteworthy
shortcomings in the process of care are evident in this case.
First, the physician formulated the incorrect assumption that ACE
inhibitor therapy had been previously overlooked. Phrased
differently, he had insufficient information about the patient's
previous medical treatment and previous response to it. Although we
generally collect such information from the patient, any clinician
will attest that doing so is far from foolproof. Real-time access
to the patient's past medical history would have revealed his
previous intolerance of ACE inhibitors, especially if the record
contained a notes field or linkage to laboratory data. Indeed, even
if the record contained only a chronological listing of medication
use, the ED physician could have identified previous exposure to an
ACE inhibitor. Regardless of whether the patient knew the reason
why the drug was discontinued, awareness of the previous exposure
would have led the ED physician to be wary of reinstituting

In this patient's case, the absence of an ACE
inhibitor from the medication profile is so glaring that it begs
the question, "Why is it not there?" Indeed, the absence of an
essential medication should generally raise a warning flag for
physicians new to the patient's care. Although the initiation of an
ACE inhibitor is understandable, a greater deficiency in this
patient's care was the failure to communicate the treatment change
to the primary care physician, who almost certainly would have
stopped the drug or, at a minimum, made provisions to monitor the
patient closely.

A second shortcoming was the absence of an
appropriate monitoring plan. Although ACE inhibitors are generally
well tolerated, like most drugs, their most worrisome adverse
effects (hypotension, renal insufficiency, angioedema, and
hyperkalemia) tend to occur early in therapy.(4) The front-loading of adverse events, which is
characteristic of most drugs, highlights the importance of early
monitoring for safety and tolerability. This is rarely the role of
the emergency physician, but it is incumbent on a new prescriber to
ensure that an appropriate monitoring strategy is in place.

Clinicians who read this case may ask, "How often
does severe hyperkalemia complicate drug treatment with an ACE
inhibitor?" The best answer is probably, "More often than clinical
trials suggest." The incidence of hyperkalemia is heavily
influenced by multiple factors, including the dose of the offending
drug(s), use of concomitant therapies, and comorbid illnesses,
particularly renal disease and diabetes mellitus.(1,2,5) Drugs that can contribute to the development of
hyperkalemia are shown in the Table. A patient with left ventricular systolic
dysfunction and diabetes who is receiving a maximal dose of an ACE
inhibitor and 25 mg of spironolactone can have up to a 20% chance
of experiencing significant hyperkalemia (K greater than 6.0 mEq/L)
early in the course of treatment, depending on other risk
factors.(6) How
often patients actually die from hyperkalemia is a matter of
speculation—because patients with severe hyperkalemia may die
suddenly as outpatients, their deaths are often misattributed to
heart disease rather than an adverse effect of therapy.

There are three main reasons why the incidence of
hyperkalemia in the "real world" is considerably higher than that
seen in randomized clinical trials (RCTs). First, RCTs typically
enroll healthier patients, systematically excluding those with
other risk factors for hyperkalemia (eg, advanced renal disease).
Second, RCTs restrict or prohibit the concomitant use of other
drugs that can cause hyperkalemia. Finally, patients enrolled in
RCTs are typically monitored far more closely than those in
clinical practice. All of these measures reflect the
"artificiality" of the clinical trial setting, and threaten the
generalizability of findings derived from RCTs.

With regard to drug-induced hyperkalemia, the
disconnect between clinical trials and the real world is perhaps
most striking in the example of spironolactone for the treatment of
heart failure. In the Randomized Aldactone Evaluation Study
(RALES), only 1.7% of heart failure patients treated with
spironolactone experienced hyperkalemia—an incidence not
statistically different from that of those patients randomized to
placebo (1.2%).(7) The
trial's finding that spironolactone dramatically improved morbidity
and mortality in patients with systolic heart failure led to an
abrupt increase in spironolactone utilization but also resulted in
thousands of additional hospitalizations involving
Moreover, there was no obvious decline in heart failure related
morbidity and mortality at the population level, perhaps because of
competing mortality from unrecognized hyperkalemia among

The luxury of hindsight allows us to speculate on
how the tragic outcome described in this case might have been
avoided. The case appears to be one of "too many cooks in the
kitchen." Although the addition of an ACE inhibitor to the
patient's regimen appeared justifiable, it was not an urgent
intervention, and, as such, it would have been logical to defer to
a physician better able to monitor the patient's response to the
drug, such as his family physician, internist, or cardiologist. The
obvious downsides of this approach are the delay to treatment and
the possibility that the therapy may again be overlooked. Because
of these concerns, another strategy would have been to prescribe
only a few days' worth of the drug and instruct the patient to
contact his primary care physician soon after discharge. It is
highly unlikely that this approach would have resulted in serious
harm. Regardless of which strategy was selected, a quick phone call
to the patient's physician would have intercepted and avoided the
catastrophic outcome in this case.

Take-Home Points

  • The addition of a new medication
    requires monitoring for adverse drug events, which typically occur
    early in the course of treatment.
  • Medication changes should always be
    communicated promptly to the patient's primary care provider, who
    is usually best positioned to monitor for adverse events and
    response to treatment.
  • When a medication is conspicuously
    absent from a patient's regimen, the physician should consider
    whether its absence is intentional.
  • Patients enrolled in clinical trials
    often derive more dramatic benefits from drug treatment and
    experience fewer adverse events than those in real world

David N. Juurlink BPhm, MD, PhD
Staff Physician, Divisions of General Internal Medicine and
Clinical Pharmacology
Sunnybrook Health Sciences Centre, Toronto
Assistant Professor, Departments of Medicine, Pediatrics, and
Health Policy, Management, and Evaluation
University of Toronto


1. Hollander-Rodriguez JC, Calvert JF Jr.
Hyperkalemia. Am Fam Physician. 2006;73:283-290.
[go to PubMed]

2. Evans KJ, Greenberg A. Hyperkalemia: a review.
J Intensive Care Med. 2005;20:272-290.
[go to PubMed]

3. Jarman PR, Mather HM. Diabetes may be
independent risk factor for hyperkalaemia. BMJ. 2003;327:812.
[go to PubMed]

4. Sica DA. Angiotensin-converting enzyme
inhibitors side effects—physiologic and non-physiologic
considerations. J Clin Hypertens (Greenwich). 2004;6:410-416.
[go to PubMed]

5. Juurlink DN, Mamdani MM, Lee DS, et al. Rates
of hyperkalemia after publication of the Randomized Aldactone
Evaluation Study. N Engl J Med. 2004;351:543-551. [go to PubMed]

6. Effectiveness of spironolactone added to an
angiotensin-converting enzyme inhibitor and a loop diuretic for
severe chronic congestive heart failure (the Randomized Aldactone
Evaluation Study [RALES]). Am J Cardiol. 1996;78:902-907. [go to PubMed]

7. Pitt B, Zannad F, Remme WJ, et al. The effect
of spironolactone on morbidity and mortality in patients with
severe heart failure. Randomized Aldactone Evaluation Study
Investigators. N Engl J Med. 1999;341:709-717. [go to PubMed]


Table. Common Drug Causes of



Aldosterone antagonists (spironolactone,

Dose-dependent; incidence of hyperkalemia
can exceed 20% at higher doses in susceptible patients

ACE inhibitors


Angiotensin receptor antagonists


Beta-adrenergic antagonists


Cyclosporine, tacrolimus


Digoxin (acute overdose)

Hyperkalemia following acute overdose
predicts poor outcome


Can occur with prophylactic doses (eg,
5000 units BID)

Nonsteroidal anti-inflammatory drugs

Patients with compromised renal perfusion
(eg, volume contraction, congestive heart failure) at greatest



Potassium supplements


Potassium-sparing diuretics (amiloride,

Hyperkalemia can occur even when combined
with a thiazide

Salt substitutes





Amiloride-like effect on distal tubule;
occurs at standard doses in otherwise well patients