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\begin{document}

\title{Calcium-Channel Blockers in Patients with Radial Artery Grafts.}



\author[1]{Marco Moscarelli}%
\author[2]{Mario Gaudino}%
\affil[1]{GVM Care and Research}%
\affil[2]{NewYork-Presbyterian Hospital/Weill Cornell Medical Center}%


\vspace{-1em}



  
  \date{June 17, 2024}


\begingroup
\let\center\flushleft
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\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
The use of radial artery (RA) grafts for coronary bypass surgery has
recently gained newer attention since it has been associated with
significant reduction in the risk of midterm cardiac events.
Surprisingly the use on the RA graft as second `best' conduit has been
limited among the surgical community. There may be several explanations
for the little popularity of the RA graft; one of the reasons that could
prevent surgeons to include the RA in the daily surgical armamentarium
it is that patients with RA grafts may require postoperative
calcium-channel blocker (CB) therapy. Due to the thick muscular wall, it
seems possible that the RA would needs CB in order to prevent spasm and
ameliorate patency. CBs are, however, associated with important side
effects; also they have hypotensive effect that can hamper the use of
other therapy such as beta-blocker or angiotensin-converting enzyme
inhibitors. The evidence supporting the use of CB after RA graft (either
in the early phase or as chronic calcium-blocker (CCB)) is weak. A the
post-hoc analysis from the `RADIAL' (Radial Artery Database
International ALliance), showed that in patients with RA, the use of CB
for at least 12 months was associated with better clinical and
angiographic outcomes at mid-term follow-up, but confounders and bias
may be responsible for the reported findings (as healthier patients are
more likely to tolerate CB) . This review aims to summarize current
evidences available on the topic and to serve as benchmark for
evidence-based decision-making for CB prescription after RA grafting.%
\end{abstract}%



\sloppy


\textbf{Introduction}

The first use of the RA as conduit for coronary artery bypass grafting
is dated back in 1973 when Carpentier and colleagues published a case
series of 30 patients\textsuperscript{1}; the authors explored the RA
potential due to the larger diameter, ease of dissection and generally
more suitability for suturing. Ten months after the operation all the
graft were opened, however they warned against early optimism because it
needed to be `ascertained whether the arterial conduits were threatened
by the same modifications as those observed in the venous
grafts'\textsuperscript{2}. Later on, in fact, the authors advised RA
use to be discontinued because of a 30\% incidence of graft occlusion.

Shortly after, other Authors also reported high rates of spasm and early
occlusion and eventually the RA was abandoned for some
times\textsuperscript{3}.

Out of serendipity, almost 20 years later, a patient in whom
postoperative angiography showed total occlusion was restudied and
surprisingly the RA was fully patent, most importantly, with no
evidences of atherosclerotic disease. Three other patients were
re-studied, with similar angiographic results. These findings attracted
newer attention of the potential use of RA as alternative graft for
coronary surgery. Hence, Carpentier restarted the RA use, this time
using CB, during and after the operation\textsuperscript{2} and in 1992,
published a paper titled: `Revival of the radial artery for coronary
artery bypass grafting', where significant improved patency was
reported\textsuperscript{4}.

It was suggested that the `key' for preserving RA patency perhaps was
the use of CB since the very early start of the harvesting and the
prescription as chronic antispastic agents. The concern of spasm with
the RA use is indeed related to its unique histologic structures that
significantly differ from all the other conduits routinely used for
CABG.

\textbf{The anatomy and morphology of the radial artery}

Arteries can be classified into three types: a) type 1: `somatic' b)
type 2: `splanchnic' c) type 3: `limb arteries'\textsuperscript{5, 6}.
The RA is an example of type 3 artery. As the other arteries, the RA has
three layer of tunica. The tunica intima is a thin layer with a
prominent internal elastic membrane. The tunica media contains myocytes,
connective tissue and elastic fibers. The tunica adventitia is very
prominent and mainly consists of collagen and elastic fibers, fibroblast
and clusters of smooth muscle cells. Notably, there are also adventitial
sympathetic and parasympathetic nerves that might be involved in
arterial spasm.

The RA is also defined as `muscular artery' given the abundant myocytes
in the media layer \textsuperscript{7}. The more muscular media compared
to the left internal mammary artery (LIMA) is the theoretical background
for the described concerns of RA spasm\textsuperscript{8}. Chester et
al. demonstrated that there are more muscle cells in the proximal RA
vessel compared to the distal RA, as well as variation in the profile of
adrenoceptors along the RA vessel\textsuperscript{9}.

Notably, the RA vasa vasorum do not penetrate into the media and
nutrients and oxygen are provided by luminal diffusion; this may suggest
that its use as free graft should not be subjected to ischemic events
over the long term. However that was challenged by other studies. van
Son and colleagues measured a mean width in the media of the RA
approximately 500 \selectlanguage{greek}μ\selectlanguage{english}m, as opposed to 330 \selectlanguage{greek}μ\selectlanguage{english}m for that of the LIMA, 280 \selectlanguage{greek}μ\selectlanguage{english}m
for that of the gastroepiploic artery and 240 \selectlanguage{greek}μ\selectlanguage{english}m for the inferior
epigastric artery\textsuperscript{10}. These authors suggested that the
RA thick media layer can be prone to fibrosis by the time, given the low
oxygen penetration at this level\textsuperscript{10}.

Local factors and systemic hormones can modulate RA vasoconstriction
acting at the level of the receptors in the vascular smooth cells. The
RA endothelium is pivotal in regulating smooth muscle
activity\textsuperscript{5}. Vasodilation in fact can be achieved by the
release of endothelium derived nitric oxide, prostaglandin and
prostacyclin. Endothelin -1, thromboxane A2 and prostaglandin 2a are
among the most potent vasoconstrictors. In terms of systemic hormones,
angiotensin II and arginine vasopressin are both potent vasoconstrictor
even at low concentration acting by opening calcium channels and via the
\selectlanguage{greek}α\selectlanguage{english}1-adrenergic receptor\textsuperscript{5}.

Remarkably, there is also evidence of cross-talk between signaling
pathway that mediate vascular contraction and those that are involved
with muscle cell growth; RA vessel contraction and spasm can be an
important step in the activation of growth-promoting
pathways\textsuperscript{11}.

There are some concerns with regard to pre-existing disease in the
radial artery; analysis from histological specimens from 177 radial
arteries showed increased prevalence of intimal thickening, medial
sclerosis and calcification in the radial artery compared to other
conduits\textsuperscript{12}.

In summary, the functional and morphological anatomy of the RA is very
complex and the way it reacts to internal or external stimuli remains,
also, not fully understood. There are a number of mechanisms that can be
responsible for vasodilation and vasoconstriction; thereby, it is
unlikely that a single agent could completely eliminate RA spasm.

\textbf{Best evidence topics (BETs) supporting the use of CB after RA
graft}

There are few randomized controlled trials (RCT) and some comparative
studies that investigated the early and chronic role of CB after RA
grafting (Table 1). However, given the high patency rate of the RA
grafts, it is possible that all the published studies were largely
underpowered to detect even moderate differences in outcome.

In Broadman et al. study\textsuperscript{13}, sixty patients underwent
post operative angiography between 1 day and 40 weeks; of these 28 were
on CB. Patency rate of the radial arteries was 95.7\% and there was no
association with CB usage.

Acar et al.\textsuperscript{3} followed up 50 patients. At long-term
follow-up angiography (5-7 years) there were no differences in terms of
graft failure among patients on CB treatment (N=27) versus the one who
had not CB (N=23).

Possati et al\textsuperscript{14} followed up 90 patients with RA. All
patients received diltiazem for a year postoperatively and 51 patients
stopped the medication during the follow-up. There was no difference in
graft patency between patients who continued or suspended CB. The same
group reported similar results in 2003\textsuperscript{15}. Similarly,
Arena et al. did not find differences in terms of graft patency in
patients with or without 6-months CB therapy\textsuperscript{16}.

Shapira et al.\textsuperscript{17} randomized 161 patients to
postoperative diltiazem or nitrates; key in-hospital and follow-up
clinical end points such as mortality, major morbidity, myocardial
infarction, use of inotropic agents and need for cardiac
catheterization, and reintervention were similar between the two groups.

A 2001 RCT from Gaudino et al.\textsuperscript{18} assigned 57 and 63
patients to early regimen (1 year) and to chronic regimen CB
respectively. After 5 years, patients were reassessed clinically and by
stress myocardial scintigraphy; 87 of them were re-studied
angiographically. They found no differences regarding either the
clinical and scintigraphic results or the RA angiographic status. They
concluded that after the first post-operative year the continuation of
CB did not affect RA graft patency or clinical and scintigraphic
results.

In 2005, the same author randomized 53 and 47 patients to receive and to
no receive CCB immediately after RA grafting\textsuperscript{19}. At
1-year follow-up all patients were reassessed clinically and
scintigraphically; 83 of them were re-studied angiographically. Again,
no differences in terms of clinical outcome, scintigraphic result and
patency rate was found between groups.

Gaudino et al. in fact questioned the chronic use of CB since they
demonstrated that 1 year after implantation in the coronary artery
circulation, the RA tends to lose the muscular component, becoming
similar to the LIMA\textsuperscript{20}.

Moran et al.\textsuperscript{21} followed-up 63 and 52 patients after RA
grafting with and without CB respectively. Coronary angiographies were
obtained at 1-year in 50 patients. No differences were observed for
clinical and angiographic end points in the patients that received CB
compared with those who had not.

Cameron et al.\textsuperscript{22} performed angiogram 5 years post RA
grafting in 50 patients; 37 of these patients received CB. The patency
rate was high (89\%) and no correlation with CCB usage was found.

A post-hoc analysis of the Radial Artery Patency
Study\textsuperscript{23} found that among 440 RA patients, the
incidence of RA spasm was not associated with the compliance with the
prescribed postoperative CB, although compliance with CB use was high
(419 of 440 patients).

Finally, a post-hoc analysis of the Radial Artery Database International
ALliance analyzed\textsuperscript{24} patient-level database included
732 patients (502 on CCB). At median follow-up of 55 months, CCB therapy
of at least 1 year was found to be associated with significantly lower
risk of MACE and RA graft occlusion.

Nevertheless, despite the lack of definitive evidences, the use of CB
after RA grafting is considered `routine' in many centers. A 2003 survey
of Canadians cardiac units showed that the vast majority of the surgeons
and physicians prescribed CB or other forms of anti-spastic therapy
after RA grafting\textsuperscript{25}.

\textbf{Table 1. Best evidences Topics (BETs): `Calcium-channel use
after RA grafting'.}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Study, Year}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Study type}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Calcium Channel Blocker}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Groups}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Follow-up}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Conclusion}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Broadman et al. Sample size=60 1996\textsuperscript{13}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case control\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diltiazem 240 mg daily\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
a) N=28 with CB b) N=28 no CB\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Mean 3-months\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
No difference in terms of patency rate between the two groups\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Acar et al\textsuperscript{3} Sample size=50 1998\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case control\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diltiazem 250 mg daily\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
a) N=27 with CB b) N=23 no CB\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
4/7-years\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
No differences in terms of graft failure\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Possati et al.\textsuperscript{14} Sample size=68 1998\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case-control\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diltiazem 120 mg twice a day\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
After the 1 year those without scintigraphic or angiographic evidence of
RA territory ischemia assigned to: a) N=29 continued CB b) N=31
suspended CB\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
5-years\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
No differences in RA graft status could be shown between groups who
continued or suspended therapy with calcium channel blockers after 1
year.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Arena et al Sample size=50 2000\textsuperscript{16}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
RCT\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Nifedipine 40 daily for 6 months post-op\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
a) N=26 with CB b) N=24 no CB\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
16-24 months\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
No difference in terms of patency rate between the two groups\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Shapira et al.\textsuperscript{17} Sample size=161 2000\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
RCT\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diltiazem and GTN\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
a) N=77 patients with diltiazem infusion for 24 h and daily for 6 months
thereafter n=77 b) N= 84 patients with GTN infusion for 24 h and daily
nitrate therapy for 6 months thereafter.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
6-months\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Major in-hospital and follow-up clinical end points (mortality, major
morbidity, myocardial infarction, use of inotropic agents, the need for
cardiac catheterization, and reintervention) similar between the study
groups\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Gaudino et al. \textsuperscript{18} Sample size=120 2001\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
RCT\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diltiazem 120 mg/day\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
a) N=57 patients suspended CB after 1 year b) N=63 patients with chronic
CB use\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
5 -year\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
No difference in graft patency, graft reactivity, myocardial ischemia or
clinical outcomes\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Moran et al.\textsuperscript{21} Sample size=115 2001\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case-control\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diltiazem 1 \selectlanguage{greek}μ\selectlanguage{english}g/kg/min intraoperatively then 180 mg/day for 1 year\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
a) N=63 patients with CB b) N=52 patients with no CB\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
1-year\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
The degree of the native coronary artery stenosis influenced the patency
rate of RA, independent of the CB\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Possati et al.\textsuperscript{15} Sample size=90 2003\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case-control\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diltiazem 120 mg daily\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
After 1 year, a) N=51 patients stopped CB b) N=49 patients on CB\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
105\selectlanguage{ngerman}±9 months\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
No differences in graft patency between two groups\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Cameron et al.\textsuperscript{22} Sample size=50 2004\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case-control\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diltiazem / amlodipine / verapamil /nifedipine\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
a) N=37 with CB b) N=23 no CB\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
5-years\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
No correlation found between CB usage and angiographic patency\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Gaudino et al.\textsuperscript{19} Sample size=100 2005\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
RCT\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diltiazem 120 mg daily\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
a) N=53 patients with CB early regimen b) N=47 patients with no CB\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
1-year\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
No difference graft patency / reactivity / ischemia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Radial Artery Patency Study\textsuperscript{23} Sample size=440
2006\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
RCT Post-hoc analysis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Nifedipine for 6 months post-op\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
a) N=419 patients with compliance to CB b) N=21 patients with no
compliance to CB\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
1-year\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
The incidence of string sign (RA spasm) was not affected by the
compliance with the prescribed CB.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Radial Artery Database International ALliance\textsuperscript{24} Sample
size=732 2019\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
RCT Post-hoc analysis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diltiazem / amlodipine\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
a) N=502 patients with CB B) N=230 patients with no CB\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Median angiographic follow-up 55 months\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
CB therapy was found to be consistently associated with a significant
lower risk of MACE and RA graft occlusion\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CB: Calcium-channel blocker. MACE: Major adverse cardiac events. RCT:
randomized controlled trial.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CB: Calcium-channel blocker. MACE: Major adverse cardiac events. RCT:
randomized controlled trial.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CB: Calcium-channel blocker. MACE: Major adverse cardiac events. RCT:
randomized controlled trial.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CB: Calcium-channel blocker. MACE: Major adverse cardiac events. RCT:
randomized controlled trial.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CB: Calcium-channel blocker. MACE: Major adverse cardiac events. RCT:
randomized controlled trial.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CB: Calcium-channel blocker. MACE: Major adverse cardiac events. RCT:
randomized controlled trial.\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Choice of calcium-channels blockers after RA grafting and side
effect}

There is a wide range of CB; however, there are three main chemically
divergent groups: dihydropyridines (eg, nifedipine, amlodipine,
nicardipine, clevidipine and nicorandil), phenylalkylamines (eg,
verapamil), and benzothiazepines (eg, diltiazem)\textsuperscript{26}.

The choice of CB to prevent RA spasm has been empirical.

At least theoretically, all CB derivatives can be used to prevent RA
graft spasm; nevertheless it has been demonstrated that dihydropyridine
are the most potent vasodilator\textsuperscript{27}. However, the vast
majority of the studies published in literature used diltiazem as
antispasmodic agent (table 1).

He and colleagues in a in-vitro study found that nifedipine was
19.5-fold more potent than verapamil and 31.6-fold more potent than
diltiazem in RA precontracted with potassium; also, its efficacy on
prevention of RA spasm was shown by the observation that at the usual
plasma concentration, nifedipine significantly reduced RA contraction,
whereas neither verapamil nor diltiazem had any effect on the RA
contraction at equal concentration\textsuperscript{26}.

Diltiazem may have significant negative chronotropic and inotropic
effects. Its early use can increase the requirement for temporary
cardiac pacing in the post-operative period.

Amlodipine is a more selective CB, thereby with less effect on the
myocardium.

However, Kloner et al.\textsuperscript{28} reported that in patients
with amlodipine, edema occurred in 24\%, headache in 8.8\% and in
fatigue and dizziness in \textgreater{}4\%.

Notably, the potential hypotensive effect of the CB may preclude the use
of other secondary prevention therapies such as beta-blockers or
angiotensin-converting enzyme inhibitors.

Polypharmacy is also an important concern and has been associated with
increased risk of cardiac events\textsuperscript{29}.

\textbf{Key factors influencing the RA patency}

Besides the CB prescription, whose utility is still under investigation,
there are other factors that might influence RA graft patency or at
least `interact' with the CB in order to contribute to RA
longevity\textsuperscript{30}. Briefly, those are:

a) appropriate coronary target selection b) meticulous and scrupulous
harvesting technique (either open or endoscopic) and a c) a general `no
touch technique', avoiding hyperinflation of the conduits that can lead
to potential for damage of the RA intima and internal elastic lamina.

With regard to target selection, rather than the location of the target
vessel it seem far more important to consider the severity of the
coronary stenosis; the reversal of one case of string sign concomitant
with the progression of the coronary stenosis, although anecdotal,
further underscore the influence of native, competitive flow on RA
graft\textsuperscript{15}. Royse and
colleagues\textsuperscript{31}defined 70\% coronary stenosis as the
`cut-off' point; below this degree of stenosis the long-term patency of
the RA was found to be significantly reduced. Desai and colleagues
recommended the use of RA graft only for severely stenotic vessel
(\textgreater{}90\%)\textsuperscript{32}.

The most common adopted vasodilators for intraoperative dilatation
during RA harvesting are CB, papaverine, nitrates and phenoxybenzamine,
without clear evidence of superiority of one of
them\textsuperscript{33}. To date, no significant advantages related to
skeletonizaton of the conduit, endoscopic harvesting, or utilization of
the harmonic scalpel during surgical harvesting have been
reported\textsuperscript{33}; yet it seem advisable during graft
preparation, to avoid hyperinflation and distension of the conduit since
would result in damage of the endothelium and the elastic laminae.

\textbf{Conclusions}

Recent studies have demonstrated superior performance of RA as second
conduit for CABG\textsuperscript{34}. Nevertheless, it remains unclear
whether its patency rate is related to correct indications (e.g.
critical coronary artery stenosis), less invasive and/or no-touch
harvesting techniques or to the use of antispasmodic drugs.

There are some evidences that support the use CB to ameliorate RA
patency\textsuperscript{24}, however given the lack of large randomized
trials on the specific topic (CCB versus no-CCB), final conclusions and
recommendations cannot be drawn.

Importantly, the side effects of CB grafting are not negligible and
should be taken into account in clinical decision-making.

Finally, understanding the triggers and mechanisms that regulate RA
vessel tone and its response to endogenous and exogenous stimulation is
pivotal in optimizing RA use as bypass conduit.

\textbf{Abbreviations}

CABG= Coronary artery bypass grafting

CB= Calcium-channel blocker

CCB= Chronic calcium-channel blocker

LIMA= Left internal mammary artery

RA= Radial artery

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