ACC/AHA 2007 guideline update for the

mortality rates. Retrospective analysis of the non–Q-wave
MI subset of patients in the Multicenter Diltiazem Postinfarction
Trial (MDPIT) suggested similar findings (334).
The Holland Interuniversity Nifedipine/metoprolol Trial
(HINT), tested nifedipine and metoprolol in a 2 2
factorial design in 515 patients (327). The study was
stopped early because of concern for harm with the use of
nifedipine alone. In contrast, patients already taking a beta
blocker appeared to benefit from the addition of nifedipine
(risk ratio [RR] 0.68) (335).
Meta-analyses combining UA/NSTEMI studies of all
CCBs have suggested no overall benefit (322,336), whereas
those excluding nifedipine (e.g., for verapamil alone) have
reported favorable effects on outcomes (332). Retrospective
analyses of DAVIT and MDPIT suggested that verapamil
and diltiazem can have a detrimental effect on mortality
rates in patients with LV dysfunction (329,330). In contrast,
verapamil reduced diuretic use in DAVIT-2, (333). Furthermore,
subsequent prospective trials with verapamil administered
to MI patients with HF who were receiving an
ACE inhibitor suggested a benefit (330,337). The Diltiazem
as Adjunctive Therapy to Activase (DATA) trial also
suggested that intravenous diltiazem in MI patients can be
safe; death, MI, and recurrent ischemia were decreased at 35
d and 6 months (338).
In summary, definitive evidence for a benefit of CCBs in
UA/NSTEMI is predominantly limited to symptom control.
For immediate-release nifedipine, an increase in serious
events is suggested when administered early without a beta
blocker. The heart rate–slowing CCB drugs (verapamil and
diltiazem) can be administered early to patients with UA/
NSTEMI without HF without overall harm and with
trends toward a benefit. Therefore, when beta blockers
cannot be used, and in the absence of clinically significant
LV dysfunction, heart rate–slowing CCBs are preferred.
Greater caution is indicated when combining a beta blocker
and CCB for refractory ischemic symptoms, because they
may act in synergy to depress LV function and sinus and AV
node conduction. The risks and benefits in UA/NSTEMI
of newer CCBs, such as the dihydropyridines amlodipine
and felodipine, relative to the older agents in this class that
have been reviewed here, remain undefined, which suggests
a cautious approach, especially in the absence of beta
blockade.
3.1.2.5. INHIBITORS OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
Angiotensin-converting enzyme inhibitors have been shown
to reduce mortality rates in patients with MI or who
recently had an MI and have LV systolic dysfunction
(339–341), in patients with diabetes mellitus with LV
dysfunction (342), and in a broad spectrum of patients with
high-risk chronic CAD, including patients with normal LV
function (343). Follow-up of patients with LV dysfunction
after MI in the TRACE (TRAndolapril Cardiac Evaluation)
trial showed that the beneficial effect of trandolapril on
mortality and hospitalization rate was maintained for at
Anderson et al ACC/AHA UA/NSTEMI Guideline Revision e191
Downloaded from
circ.ahajournals.org by on September 22, 2007
least 10 to 12 years (344). A systematic review assessing
potential ASA–ACE inhibitor interactions showed clinically
important benefits with ACE inhibitor therapy, irrespective
of whether concomitant ASA was used, and only
weak evidence of a reduction in the benefit of ACE
inhibitor therapy added to ASA (345); these data did not
solely involve patients with MI. Accordingly, ACE inhibitors
should be used in patients receiving ASA and in those
with hypertension that is not controlled with beta blockers.
Recent data on ACE inhibitor patients with stable CAD are
summarized in the section on long-term medical therapy
(see Section 5.2.3).
In patients with MI complicated by LV systolic dysfunction,
HF, or both, the angiotensin receptor blocker
valsartan was as effective as captopril in patients at high
risk for cardiovascular events after MI. The combination
of valsartan and captopril increased adverse events and
did not improve survival (346). Although not in the acute
care setting, treatment of patients with chronic HF with
candesartan (at least half of whom had an MI) in the
CHARM (Candesartan in Heart failure Assessment in
Reduction of Mortality)-Overall program showed a reduction
in cardiovascular deaths and hospital admissions
for HF, independent of ejection fraction or baseline
treatment (347).
The selective aldosterone receptor blocker eplerenone,
used in patients with MI complicated by LV dysfunction
and either HF or diabetes mellitus, reduced morbidity and
mortality in the Eplerenone Post-acute myocardial infarction
Heart failure Efficacy and SUrvival Study (EPHESUS)
(348). This complements data from the earlier Randomized
ALdactone Evaluation Study (RALES), in which aldosterone
receptor blockade with spironolactone decreased morbidity
and death in patients with severe HF, half of whom
had an ischemic origin (349). Indications for long-term use
of aldosterone receptor blockers are given in Section 5.2.3.
3.1.2.6. OTHER ANTI-ISCHEMIC THERAPIES
Other less extensively studied therapies for the relief of
ischemia, such as spinal cord stimulation (350) and prolonged
external counterpulsation (351,352), are under evaluation.
Most experience has been gathered with spinal cord
stimulation in “intractable angina” (353), in which anginal
relief has been described. They have not been applied in the
acute setting for UA/NSTEMI.
The K ATP channel openers have hemodynamic and
cardioprotective effects that could be useful in UA/
NSTEMI. Nicorandil is such an agent that has been
approved in a number of countries but not in the United
States. In a pilot double-blind, placebo-controlled study
of 245 patients with UA, the addition of this drug to
conventional treatment significantly reduced the number
of episodes of transient myocardial ischemia (mostly silent)
and of ventricular and supraventricular tachycardia (354).
Further evaluation of this class of agents is underway.