You are on page 1of 5

ADULT CARDIAC

Efficacy of Aggressive Lipid Controlling Therapy


for Preventing Saphenous Vein Graft Disease
Mitsumasa Hata, MD, PhD, Tadateru Takayama, MD, Akira Sezai, MD,
Isamu Yoshitake, MD, Atsushi Hirayama, MD, and Kazutomo Minami, MD
Departments of Cardiovascular Surgery, and Cardiology, Nihon University School of Medicine, Tokyo, Japan

Background. We assessed the efficacy of aggressive lipid


controlling therapy (ALCT), which maintains low-density
lipoprotein cholesterol (LDL-C) below to 80 mg/dL and
LDL/high-density lipoprotein cholesterol (HDL-C) ratio
less than 1.5 for preventing postcoronary bypass (CABG)
saphenous vein graft (SVG) diseases by using intracoronary angioscopy.
Methods. Twenty-one patients after CABG were divided into two groups: group I consisted of 10 patients
whose serum LDL-C level and LDL/HDL could be controlled less than 80 mg/dL and 1.5, respectively, by
rosuvastatin for about one year; group II consisted of
11 patients whose LDL-C level and LDL/HDL have
been higher than 100 mg/dL and 2.5, respectively,
regardless of having medication of pravastatin. Twentyseven SVGs were assessed by intravascular ultrasound (IVUS) and angioscopy on postoperative 12 to 16
months.

Results. The serum LDL-C level (I: 64.1 vs II: 130.2


mg/dL) and LDL/HDL (I: 1.36 vs II: 2.64), and high
sensitive C-reactive protein (I: 0.045 0.100 vs II: 0.116
0.020 mg/dL) were significantly lower in group I. In
group II, IVUS detected eccentric plaques in 11 (78.6%) of
14 SVGs. Furthermore the angioscope showed yellow
plaque in all 14 SVGs (100%) and 11 (78.6%) of them had
thrombi. On the other hand, in group I, all 13 SVGs had
no eccentric, yellow plaques or thrombi and the intima
was entirely clear white.
Conclusions. Prophylactic treatment for yellow plaque
and thrombus formation are extremely important in the
development of early and late SVG disease. Aggressive
lipid controlling therapy is quite attractive to avoid post
CABG SVG disease and may be effective to maintain the
long-term graft patency.
(Ann Thorac Surg 2009;88:1440 4)
2009 by The Society of Thoracic Surgeons

tivessel diseases, it is increasingly important to maximize


the long-term SVG patency in order to optimize longterm surgical outcome.
Plaque rupture with thrombus formation is the major
cause of long-term SVG disease [8, 9]. Lowering of low
density lipoprotein cholesterol (LDL-C) below 100 mg/dL
has been shown to be effective for reducing the progression of atherosclerosis in SVG [10]. High density lipoprotein cholesterol (HDL-C) has also been associated with a
protective effect on atherosclerosis in carotid arteries [11].
No studies to date have investigated the efficacy of
aggressive statin therapy on angioscopic progression
after CABG, SVG disease. The aim of this study was to
identify the morphologic changes in SVG by intracoronary ultrasound and angioscopy, and to assess the efficacy of aggressive lipid controlling therapy with rosuvastatin versus moderate therapy with pravastatin.

espite the advances in the relevant technologies and


techniques, nearly 25% of saphenous vein grafts
(SVG) become occluded within 1 year after surgery, and
50% of SVGs fail within 10 years [1, 2]. Gansera and
colleagues [3] reported that the incidence of SVG occlusion was twofold higher than that of the internal thoracic
artery in symptomatic patients [3]. Even though the
patient has no coronary events, more than 20% of SVG
have been occluded for 10 years after surgery [4]. However, the ready availability of SVGs still accounts for their
use in over 70% of coronary artery bypass graft (CABG)
surgery, particularly for the emergency or multiple vessel
disease patients. Recently, several investigators reported
that aggressive risk factor control, together with appropriate secondary preventive medication, has shown to
slow progression of SVG atherosclerosis and the longterm patency of SVG was not very different than other
arterial conduits except for the internal thoracic artery [5,
6]. Furthermore, Souza and colleagues [7] showed the
long-term SVG patency was 90% by harvesting with
minimum trauma. Because of the need of the cardiac
surgeon to perform complete revascularization for mul-

Accepted for publication June 1, 2009.


Address correspondence to Dr Hata, Department of Cardiovascular
Surgery, Nihon University School of Medicine, 30-1 Ooyaguchi Kamimachi Itabashi-ku, Tokyo, 173-8610, Japan; e-mail: mihata@med.nihon-u.
ac.jp.

2009 by The Society of Thoracic Surgeons


Published by Elsevier Inc

Patients and Methods


Twenty-one patients who have been followed-up more
than 12 months after CABG were angiographically assessed. All procedures were carried out with traditional
on-pump CABG using the left internal thoracic artery,
one radial artery, and SVGs. In CABG, we usually used
the left internal thoracic artery for the left anterior
descending artery or big diagonal branch, and one radial
0003-4975/09/$36.00
doi:10.1016/j.athoracsur.2009.06.009

HATA ET AL
AGGRESSIVE LIPID CONTROL FOR SVG DISEASE

artery for the proximal right coronary artery or first


obtuse marginal branch of circumflex territory because
the radial artery length is limited. The SVG is used for the
distal part of the right coronary artery, second obtuse
marginal branch, or distal part of the left anterior descending artery. The SVG was harvested by standard
technique with scissors and clips. An endoscope was
never used for graft harvesting. Furthermore, we tried to
distend the harvested SVG with just a little pressure and
minimize the intimal damage of SVG. All the patients
underwent CABG during 2007 in our Institution. This
study was a case-controlled observational study and
Institutional Review Board approval was provided before
publication of this manuscript and reporting of the information. The matched criteria between the groups were as
follows; noninsulin user, age less than 80 years old,
receiving both aspirin 100 mg and ticlopidine 200 mg daily,
and receiving some calcium antagonists. Seventeen patients (81.0%) were male, and the average age was 65.6
10.4 years, ranging from 31 to 78. Written informed consent
was given to all patients to receive the graft assessment
by coronary angiography, intravascular ultrasound
(IVUS), and angioscopy. The coronary angioscopic catheter (Fibertech Co, Tokyo, Japan) used in the present
study is 0.73 mm in outer diameter with a fiber containing 6,000 pixels. After the SVG angiography, we carefully
put the angioscope into the distal anastomosis site of
SVG. We then observed the entire SVG intima by pulling
back the angioscope to the proximal anastomosis site.
We divided them into two groups. Group I consisted of
10 patients whose LDL-C level and LDL/HDL ratio have
been strictly maintained lower than 80 mg/dL and 1.5,
respectively, after surgery by aggressive lipid control
with rosuvastatin (5 mg) at an outpatient clinic. Group II
consisted of 11 matched patients whose LDL-C level and
LDL/HDL ratio have exceeded 100 mg/dL and 2.5, respectively, for one year after surgery treated with pravastatin 10 mg at general practitioners. Both doses of
statins were the usual starting dose of medication for
Japanese patients. In this series, all patients had started
taking statins approximately 14 days after the surgery
when they first visited the outpatient clinic. Statins were

Table 2. Laboratory Data


Variable

Group I

Group II

13.6 1.6
Study duration (month) 13.7 1.3
LDL (mg/dL)
64.1 11.9 130.2 66.1
HDL (mg/dL)
50.3 17.3
48.7 8.2
LDL/HDL ratio
1.36 0.34
2.64 1.25
TG (mg/dL)
160.2 81.0 125.8 61.1
HbA1c (mg/dL)
6.0 0.9
6.3 1.4
hsCRP (mg/dL)
0.045 0.100 0.116 0.020
a

Age
Male/female
Hypertension (%)
Diabetes (%)
Smoking (%)
Numbers of grafts
Target vessel for SVGs
LAD
CX
RCA

Group I

Group II

p Value

62.3 11.8
9/1
80
50
40
3.30 0.48

63.7 6.9
8/3
63.6
45.5
45.5
3.27 0.47

0.5624
0.3141
0.4071
0.835
0.8008
0.1315
0.7887

1
4
8

2
5
7

CX circumflex artery;
LAD left anterior descending artery;
RCA right coronary artery;
SVG saphenous vein graft.

p Value
0.5345
0.0038
0.3463
0.0036
0.2018
0.2007
0.0125

Study duration from surgery to graft assessment.

LDL low density lipoprotein cholesterol;


HDL high density
lipoprotein cholesterol;
HbA1c hemoglobin A1c;
hsCRP hypersensitive C-reactive protein;
TG triglyceride.

never discontinued until angioscopic assessment. The


serum level of LDL-C, HDL-C, and the LDL/HDL ratio
was assessed at every month. No patients in either group
received beta-blockers. We compared the two groups in
terms of serum level of cholesterols, triglyceride, hemoglobin A1c, hypersensitive C-reactive protein (hsCRP),
and the incidence of SVG diseases such as graft stenosis,
eccentric plaque, unstable yellow plaque, and thrombi by
angiography, IVUS, and angioscopy, respectively. We
assessed 13 and 14 SVGs from groups I and II,
respectively.

Statistical Examination
Results were expressed as the mean SD. Statistical
calculations were conducted using StatView (SAS Inc, Cary,
NC). Using parametric and nonparametric data, statistically
significant differences were determined using the Student t
test and Fisher exact test, respectively. A p value of less than
0.05 was considered statistically significant.

Table 1. Patient Profiles


Variable

1441

Fig 1. Yellow plaque in saphenous vein grafts detected by


angioscopy.

ADULT CARDIAC

Ann Thorac Surg


2009;88:1440 4

1442
ADULT CARDIAC

HATA ET AL
AGGRESSIVE LIPID CONTROL FOR SVG DISEASE

Ann Thorac Surg


2009;88:1440 4

Fig 4. Around the proximal anastomosis site.


Fig 2. Massive thrombus formation on the yellow plaque detected by
angioscopy.

Results
There was no difference between the groups in terms of
average age, sex, prevalence of hypertension, diabetes,
smoking, and target vessels of SVGs (Table 1). Average
postoperative study duration was approximately 14
months in both groups (Table 2). The serum LDL-C level
was significantly lower in group I (64.1 11.9 mg/dL)
compared with group II (130.2 66.1 mg/dL) (p 0.0038;
Table 2). The LDL/HDL ratio was significantly lower in

group I (1.36 0.34) than that of group II (2.64 1.25)


(p 0.0036; Table 2). The Hs-CRP was significantly lower
in group I (0.045 0.100 mg/dL) than that of group II
(0.116 0.020 mg/dL) (p 0.0125; Table 2). There was no
difference between the groups in terms of the level of
HDL, triglyceride, and hemoglobin A1c levels (Table 2).
All SVGs and other arterial grafts in both groups were
patent on graft angiography. In group II, however, IVUS
detected one or two large amounts of eccentric plaques in
a low-density echoic lesion, which length was more than
2 cm at around the mid portion of SVG intima in 11
(78.6%) out of 14 SVGs. Angioscopy demonstrated the
yellow plaques (Fig 1) on the same points of SVG intima.
Even though IVUS did not detect the plaques, the angioscopy showed some yellow plaques on the mid portion of SVG intima and finally, yellow plaques were
indicated in all 14 SVGs (100%). Furthermore, angioscope
also revealed white thrombi on the yellow plaques in 11
(78.6%) of 14 SVGs (Fig 2). Graft angiography revealed
50% to 75% stenosis in five of these SVGs with thrombi.
On the other hand, in group I, all 13 SVGs had no
eccentric, yellow plaques or thrombi, and the intima was
entirely clear white (Figs 3 and 4). The incidence of SVG
Table 3. Findings of CAG, IVUS, and Angioscopy
Variable
CAG
Stenosis in SVG
IVUS
Eccentric plaque
Angioscopy
Yellow plaque
Thrombi

Fig 3. Entire clear white intima without any yellow plaque and
thrombi detected by angioscopy. Around the distal anastomosis site.

Group I

Group II

p Value

5 SVGs (35.7%)

0.032

11 SVGs (78.6%)

0.0001

0
0

14 SVGs (100%)
11 SVGs (78.6%)

0.0001
0.0001

CAG coronary angiography;


SVG saphenous vein graft.

IVUS intravascular ultrasound;

diseases such as yellow plaque and thrombi was significantly higher in group II than in group I (p 0.0001;
Table 3). During follow-up periods, there was no coronary event in either group.

Comment
It is evident from this angioscopic study that the major
features of SVG diseases are the presence of unstable
atherosclerotic plaques and thrombi. Especially, SVG
atherosclerosis predisposes to thrombosis because of the
high content of lipids and tissue factor, chronic flow
disturbances, and associated impairment of vasodilatation. The SVG atheromas are more diffuse and vulnerable to rupture, and the major consequences of plaque
rupture in SVGs seem to be rapid platelet aggregation
and certain thrombotic occlusion [12]. Therefore, antiplatelet agents and cholesterol lowering therapy are
theoretically attractive options for the prevention of such
consequences.
In the present study, all patients received ticlopidine as
well as aspirin. Our previous study [9] showed that
ticlopidine reduced the development of SVG thrombi
caused by nonlaminar or sluggish flow within the SVG.
Several investigators have also reported that the addition
of ticlopidine to aspirin significantly inhibited high shear
stress which induced platelet aggregation [13]. In the
present study, although the patients in both groups have
received the same antiplatelet therapy, more than 70% of
SVGs in group II still had thrombi; no thrombi, on the
other hand, was detected in all group I SVGs. It should be
demonstrated that thrombi on the yellow plaques were
not only caused by platelet aggregation due to sluggish
blood flow, but also by multiple plaque rupture of vulnerable plaques [14, 15]. The predominant mechanisms
for SVG disease are intimal hyperplasia appearing from
postoperative early phase and accelerated atherosclerosis. Saphenous vein graft atherosclerosis is especially
prone to thrombi because of the high content of lipids
and tissue factor, chronic flow disturbance, and impaired
vasodilation. These SVG atheroma are more diffuse and
vulnerable to rupture, and the consequences of plaque
rupture in SVGs seem to be associated with almost
certain thrombotic occlusion [12]. Therefore, regular antiplatelet therapy is not enough to avoid SVG thrombi; it
may be more important and essential to interrupt the
development of vulnerable yellow plaques.
A post-CABG trial with angiographic assessment has
shown that aggressive lowering and maintenance of the
LDL-C level below 100 mg/dL was more effective than
moderate lowering of LDL-C in reducing the progression
of atherosclerosis in SVGs. It defined the prognostic
factors for risk of atherosclerotic progression in SVGs in
the large and well-characterized post-CABG patient population [10]. In the present study, the LDL-C level of
group I was maintained below 80 mg/dL. However, the
National Cholesterol Education Program (NCEP) Adult
Treatment Panel III guidelines now recommend achieving more aggressive target levels (an LDL-C level 70
mg/dL) in certain very high-risk secondary prevention

HATA ET AL
AGGRESSIVE LIPID CONTROL FOR SVG DISEASE

1443

patients [14]. OKeefe and colleagues (15) also proposed,


based on accumulating data from multiple populations
that do not develop atherosclerosis or coronary events,
that normal LDL-C levels are approximately 50 to 70
mg/dL. Von Birgelen and colleagues [16] further suggested that an LDL-C level of 75 mg/dL is, on average,
associated with plaque regression. Moreover, many investigators have recommended aggressive lipidlowering therapy as a recent international consensus to
keep serum LDL-C level between 70 and 80 mg/dL in
order to avoid the development of atherosclerotic
plaques [17, 18].
Nissen and colleagues [19] reported that rosuvastatin
had a strong effect on lowering the LDL-C level to less
than 70 mg/dL. Harley and colleagues [20] also described
that rosuvastatin was more effective at reducing LDL-C
levels and attaining a NCEP LDL-C goal than other
statins. In the present study, however, we mentioned the
aggressive lipid-controlling therapy rather than aggressive lipid-lowering therapy. Campeau and colleagues [21] observed that elevated plasma cholesterol
and LDL-C, as well as low HDL-C, was associated with
atherosclerotic progression in SVGs. Recently, it is important to control not only LDL-C but also HDL-C for
preventing atherosclerosis development and coronary
events. Astor and colleagues [22] suggested that a graded
association exists between lower levels of HDL-C and
were associated with increased risk of heart attack irrespective of the LDL-C levels. In fact, serum HDL-C levels
are variable. Therefore, it is essential to examine the
combined effects of higher HDL-C levels with various
levels of LDL-C, and the LDL/HDL ratio was the most
sensitive marker for the atherosclerosis progression [23].
Several studies proposed an LDL/HDL ratio of 2.0 or less
to halt the progression of atherosclerosis [24, 25], while
that of 1.5 or less produced remarkable regression of
atherosclerosis [19, 26]. In the present study, aggressive
lipid controlling therapy could keep the patients LDL/
HDL ratio less than 1.5. Furthermore, a serum LDL-C
level was maintained at approximately 60 mg/dL, which
was almost similar to the LDL-C level of that of a new
born baby [15]. Therefore, SVG endoscopy shown as
entire clear white intima in all SVGs by aggressive lipid
control looked like baby skin.

Study Limitation
This study has several limitations. It is a case control
analysis of a single institution. Therefore, the sample size
was slightly small, quantitative coronary analysis in angiography has not been conducted, and we have no data
of coagulation factors in each patient. In the aggressive
lipid controlling therapy, however, serum LDL-C and the
LDL/HDL ratio were quite strictly controlled lower than
80 mg and 1.5, respectively. These lipid controls were
much more aggressive than those of a previous report
[10]. Furthermore, as far as we know, the data from SVG
endoscopy in very high-intensity statin therapy is quite
unique and results were obviously better than regular
treatment. We have to keep observing the patients and

ADULT CARDIAC

Ann Thorac Surg


2009;88:1440 4

1444
ADULT CARDIAC

HATA ET AL
AGGRESSIVE LIPID CONTROL FOR SVG DISEASE

future studies are needed to determine the effect of the


observed changes on long-term outcome.

Ann Thorac Surg


2009;88:1440 4

12.

Conclusion
Prophylactic treatment for yellow plaque and thrombus
formation are extremely important in the development of
early and late SVG disease. Use of more effective new
generation statins is vitally important to achieve a LDL/
HDL ratio below 1.5. Aggressive lipid controlling therapy
is quite attractive to avoid post-CABG SVG disease and
the study indicated that it may be effective to maintain
the long-term graft patency.

13.

References

16.

1. Bulkley BH, Hutchins GM. Accelerated atherosclerosis: a


morphologic study of 97 saphenous vein coronary artery
bypass grafts. Circulation 1977;55:1639.
2. Kalan JM, Roberts WC. Morphologic findings in saphenous
veins used as coronary artery bypass conduits for longer
than 1 year: necropsy analysis of 53 patients, 123 saphenous
veins, and 1865 five-millimeter segments of veins. Am
Heart J 1990;119:1164 84.
3. Gansera B, Schmidtler F, Angelis I, Kiask T, Kemkes BM,
Botzenhardt F. Patency of internal thoracic artery compared
to vein graftspostoperative angiographic findings in 1189
symptomatic patients in 12 years. Thorac Cardiovasc Surg
2007;55:4127.
4. Campbell PG, Teo KSL, Worthley SG, et al. Non-invasive
assessment of saphenous vein graft patency in asymptomatic patients. Brit J Radiol 2009;82:2915.
5. Knot UN, Friedman DT, Pettersson G, Smedira NG, Li J, Ellis
SG. Radial artery bypass grafts have an increased occurrence of angiographically severe stenosis and occlusion
compared with left internal mammary arteries and saphenous vein grafts. Circulation 2004;109:2084 91.
6. Shah PJ, Bui K, Blackmore S, et al. Has the in situ right
internal thoracic artery been overlooked? An angiographic
study of the radial artery, internal thoracic arteries and
saphenous vein graft patencies in symptomatic patients. Eur
J Cardiothorac Surg 2005;27:870 5.
7. Souza DSR, Johansson B, Boj L, et al. Harvesting the
saphenous vein with surrounding tissue for CABG provides
long-term graft patency comparable to the left internal
thoracic artery: results of a randomized longitudinal trial.
J Thorac Cardiovasc Surg 2006;132:373 8.
8. Murphy GJ, Angelini GD. Insights into the pathogenesis of
vein graft disease: lessons from intravascular ultrasound.
Cardiovasc Ultrasound 2004;2:8.
9. Hata M, Sezai A, Niino T, et al. What is the optimal
management for preventing saphenous vein graft diseases?
Early results of intravascular angiographic assessment. Circ
J 2007;71:286 7.
10. The Post Coronary Artery Bypass Graft Trial Investigators.
The effect of aggressive lowering of low-density lipoprotein
cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass
grafts. N Engl J Med 1997;336:153 63.
11. Phan BA, Chu B, Polissar N, Hatsukami TS, Yuan C, Zhao
XO. Association of high-density lipoprotein levels and caro-

14.

15.

17.

18.

19.
20.

21.

22.

23.

24.

25.

26.

tis atherosclerotic plaque; noninvasive MR imaging for


characterization. Int J Cardiovasc Imaging 2007;23:337 42.
Safian RD. Accelerated atherosclerosis in saphenous vein
bypass grafts: A spectrum of diffuse plaque instability. Prog
Cardiovasc Dis 2002;44:437 48.
Isaka N, Tanigawa T, Nishikawa M, Nakano T. High shear
stress induced platelet aggregation (h-SIPA) and effects of
antiplatelet therapy. Nippon Rinsho 1998;56:2624 9.
Grundy SM, Cleeman JI, Merz CN, et al. Implications of
recent clinical trials for the National Cholesterol Education
Program (NCEP) Adult Treatment Panel III. J Am Coll
Cardiol 2004;44:720 32.
OKeefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R.
Optimal low-density lipoprotein is 50 to 70 mg/dl lower is
better and physiologically normal. J Am Coll Cardiol 2004;
43:21427.
Von Birgelen C, Hartmann M, Mintz GS, et al. Relation
between progression and regression of atherosclerotic left
main coronary artery disease and serum cholesterol levels as
assessed with serial long-term ( or 12 months) follow-up
intravascular ultrasound. Circulation 2003;108:2757 62.
Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of
intensive compared with moderate lipid-lowering therapy
on progression of coronary atherosclerosis. JAMA 2004;291:
1071 80.
Okazaki S, Yokoyama T, Miyauchi K, et al. Early statin
treatment in patients with acute coronary syndrome. Demonstration of the beneficial effect on atherosclerotic lesions
by serial volumetric intravascular ultrasound analysis during half a year after coronary event: The ESTABLISH Study.
Circulation 2004;110:1061 8.
Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very highintensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556 65.
Harley CR, Gandhi SK, Heien H, McDonough K, Nelson SP.
Lipid levels and low-density lipoprotein cholesterol goal
attainment in diabetic patients: rosvastatin compared with
other statins in usual care. Expert Opin Pharmacother 2008;
9:669 76.
Campeau L, Enjalbert M, Lesprance J, et al. The relation of
risk factors to the development of atherosclerosis in saphenous-vein bypass grafts and the progression of disease in the
native circulation. A study 10 years after aortocoronary
bypass surgery. N Engl J Med 1984;311:1329 32.
Astor BC, Lee F, Munter PM. Association of HDL cholesterol
with coronary heart disease risk across categories of LDL
cholesterol: the Atherosclerosis Risk in Communities (ARIC)
Study. J Am Coll Cardiol 2007;Mar 6:326A.
Phan BA, Chu B, Polissar N, Hatsukami TS, Yuan C, Zhao
XO. Association of high-density lipoprotein levels and carotis atherosclerotic plaque; noninvasive MR imaging for characterization. Int J Cardiovsc Imaging 2007;23:337 42.
Noike H, Hitsumoto T, Sakurai T, et al. Relationships between intravascular ultrasonographic findings and coronary
risk factors in patients with normal coronary angiography.
[In Japanese] J Cardiol 2005;45:110.
Crouse JR III, Raichlen JS, Riley WA, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in
low-risk individuals with subclinical atherosclerosis: the
METEOR Trial. JAMA 2007;297:1344 53.
Nicholls SJ, Tuzch EM, Sipahi I, et al. Statins, high-density
lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007;297:499 508.