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Three Part Question

In [patients undergoing coronary grafting], does receiving a [radial artery conduit] improve [radial artery patency]?

Clinical Scenario

You are looking after a 45-year old bricklayer with severe triple vessel disease who underwent urgent CABG using bilateral internal mammary arteries and a radial artery graft. He has progressed well and is awaiting discharge. He was on no medication on admission and asks you why he needs to have 6 weeks of Diltiazem three times per day as prescribed by your consultant. You have some difficulty justifying this medication and thus resolve to look up the literature that night.

Search Strategy

Medline1966 to Jan 2006.
[Exp coronary artery bypass/OR coronary bypass.mp/OR coronary art$ bypass.mp OR CABG.mp OR exp Thoracic surgery/]AND[exp Radial artery/ OR radial arter$.mp]AND[exp calcium channel blockers/OR calcium channel blocker$.mp/OR calcium antagonist$.mp/OR exp diltiazem/OR diltiazem.mp/OR exp amlodipine/OR amlodipine.mp OR exp nitrates/OR nitrate$.mp OR GTN.mp OR exp vasodilator agents/OR exp nitroglycerin/]

Search Outcome

The search found 98 papers. Of these papers14 represented the best evidence to answer the clinical question. Of note we included only in-vivo and clinical studies.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Guadino et al, Italy, 2005	100 patients undergoing CABG with RA were randomised to :- Ca channel blocker therapy with Diltiazem 120mg daily (CCBT) N=53 No therapy ( no CCBT) N=47	PRCT (level 1b)	At 1 year follow up, all patients were assessed clinically and with TI201 myocardial scintigraphy.	1 year clinical and scintigraphic results CCBT Clinical recurrence 1 Scintigraphic evidence of ischaemia 2 RA related ischemia 1 No CCBT clinical recurrence 0 Scintigraphic evidence of ischaemia 1 RA related ischaemia
			83 underwent control angiography.	One year angiographic results CCBT (n=42)No CCBT(n=41) Perfect RA 40 in each groups Stringed RA CCBT =1 No CCBT=0 Irregular RA CCBT=1 No CCBT=0 Occluded RA CCBT=0 No CCBT=1
			In 12 the response to endovascular serotonin infusion was evaluated	Response to Serotonin CCBT n=6 No CCBT n=6 RA diameter Pre (mm) CCBT=2.1+/-0.1 No CCBT=2.11+/-0.1 Post (mm) CCBT=1.69+/-0.32 No CCBT=1.7+/-0.31
Gaudino et al, Italy, 2001	120 patients who underwent CABG with RA who were taking diltiazem 120mg/day who at 1 year had NO scintigraphic evidence of RA territory ischemia or angiographic evidence of RA dysfunction were randomised to 2 groups:- Continuing calcium channel blockers (CCBT) n=63 Suspending calcium channel blockers (SCCBT) n=57	PRCT (level 1b)	At 5 year follow up all 120 patients were reassessed clinically and with stress scintigraphy	5 year clinical and scintigraphic results CCBT Angina recurrence 6 Scintigraphic evidence of ischaemia 11 RA related ischaemia 3 SCCBT Angina recurrence 7 Scintigraphic evidence of ischaemia 10 RA related ischaemia 2
			87 underwent angiography. (45 from CCBT gp. And 42 from the SCCBT gp.)	5 year angiographic results CCBT (n=45) SCCBT (n=42) Perfect RA CCBT=42 SCCBT =40 Stringed RA 1 in each group Irregular RA CCBT=1 SCCBT=0 Occluded RA 1 in each group
			In 15 the response to endovascular serotonin was evaluated. ( 8 from CCBT gp. And 7 from the SCCBT gp.)	Response to Serotonin CCBT RA diameter pre (mm) 2.6+/-0.41. RA diameter post (mm) 2.45+/-0.69 SCCBT RA diameter pre (mm) 2.57+/-0.35. RA diameter post(mm) 2.47+/-0.73
Shapira et al, 2001, USA	161 patients undergoing CABG with RA were randomised to 2 treatment groups:- Diltiazem infusion for 24 hrs and daily for 6 months thereafter n=77 (D) GTN infusion for 24 hrs and daily nitrate therapy for 6 months thereafter n=84 (N)	PRCT (level 1b)	MI localised to RA Territory	Nitrate group 2 pts. Diltiazem group 1pt p=0.94	No routine angiography Study groups were too small to detect significant differences between groups
			Abnormality on angiogram	Nitrate group 1 pt Diltiazem group 1pt p=0.52
			Abnormal perfusion in RA territory detected with Thallium scan n=117	Nitrate group 2 pts Diltiazem group 2pts
			Stenting to RA graft	Nitrate group 0 pts Diltiazem group 1pt
Sperti et al, 1999, Italy	A subgroup of 31 patients undergoing CABG with RA were divided in 2 groups:- Gp.1 22 patients who were on no anti anginal or calcium channel blockade therapy up to 48 hrs prior to surgery and thereafter Gp.2 9 patients on chronic diltiazem therapy and continued post operatively	Cohort Study (level 3b)	The response of the RA to 2 different concentrations of 5HT in the RA grafts in each group mean follow up 338 days for Gp.1	RA Diameter (mm):- (mean+/-SD) Baseline 2.06+/-0.48mm 1x10-6 M 5HT 1.69+/-0.46mm 1x10-5 M 5HT 1.14+/-0.79mm	Small group size especially in the diltiazem group
			mean follow up 301 days for Gp.2)	RA Diameter (mm)r:- Baseline 2.10+/-0.46mm 1x10-6 M 5HT 1.72+/-0.23mm 1x10-5 M 5HT 1.40+/-0.72 mm RA showed a marked vasoconstriction to 5HT despite the administration of diltiazem
Possati et al, 1998, Italy	68 consecutive patients who had RA conduits during CABG. All except 2 were taking calcium channel blockers diltiazem 120 mg bd. After the 1st year those without scintographic or angiographic evidence of RA territory ischemia (n=60) were randomly assigned to- 1. Continue calcium channel blockers (n=29) CCBT 2. Suspend calcium channel blockers SCCBT (n=31)	Cohort study (Level 2b)	Midterm angiographic status of RA grafts (after 5 years)	No differences in RA graft status could be shown between groups who continued or suspended therapy with calcium channel blockers after 1 year. CCBT 1 pt had string sign in the RA and 1 had irregularities in the RA SCCBT 1 patient had string sign	Subset of patient cohort from Gaudino 2001
			Clinical status	CCBT Angina recurred in 3/29. Due to RA malfunction 1/3 SCCBT Angina recurred in 3/31 Due to RA malfunction 0/3
Acar et al, 1998, France	First 102 of 910 consecutive patients undergoing CABG with a radial artery graft. Patients were followed up long term over 4-7 years. Diltiazem was initially given to all patients. At follow up 50 patients had angiography. Of these patients:- 27 were taking calcium channel blockers (CCBT) 23 had discontinued treatment for at least 6 months. (No CCBT) The study was part of a larger study that looked at early and midterm angiographic findings	Cohort study (level 3b)	At follow up (4-7 years) angiography was performed in 50 patients. 64 radial arteries were therefore followed up	At long term follow up overall patency rate was 83% for the radial artery. In the group of 27 who were on CCBT there were a 8 radial graft failures In the group of 23 who had no CCBT there were 4 graft failures P=0.31	No mention of specific patency rates for those treated with calcium channel blockers versus those who were not were not reported for early and midterm angiographic study patient groups
Brodman et al, 1996, USA	60 of 175 patients having RA as conduits during CABG had angiography. Diltiazem infusion was started immediately post operatively and then changed to oral diltiazem (up to 240 mg daily). 60 patients were followed up with angiography 28 were still taking a calcium channel blocker 32 were not on calcium channel blockers	Cohort study (level 2b)	Coronary angiography was performed a mean of 12 weeks (1 day to 40 weeks)	2 patient suffered perioperative MI-none were related to the RA graft. At follow up angiography 95.7 % of graphs were patent 86 of 90 RA grafts were perfectly patent	No control group with no CCB therapy. CCB versus No CCB patency rates not reported Not clear when diltiazem ceased in these pts.
Myers et al, 2003, Canada	A survey of Canadian surgical centres as to their antispasm regimes for patients receiving radial arteries	Survey (Level 3b )	Routine Prophylaxis	25 of 27 units use calcium channel antagonist
			Nitrate usage	12 of the 25 units also use intravenous nitrates in addition to CCBs
Possati et al, 2003, Italy	Cohort of 90 patients who received a radial artery from 1993 followed up prospectively. All patients prescribed Diltiazem 120mg/day for 1st year. 51 patients then stopped CCBs for a variety of reasons Long term angiography performed ( Mean 105 ± 9 months)	Cohort study (Level 2b)	Long term patency	74/84 (88%) perfect patency 2 irregularities, 1 string sign, 7 occluded	No group received no CCBs post-operatively. The CCB analysis is a non randomised retrospective study which is underpowered.
			IVUS assessment (5 patients)	4 perfect patency, 1 area of mild atherosclerosis
			Calcium Channel antagonist groups	CCB continued until angiogram 32/37 (89%) perfect patency, 3 occluded. 1 string sign, 1 irregularities. CCB stopped after 1 year. 42/47 (89%) perfect patency, 4 occluded, 1 irregularities.
Cameron et al, 2004, India	50 patients who received a radial artery had re-angiography at 5 years. 37/50 (74%) patients had a calcium channel blocker perioperatively. By restudy 26% of patients were still on CCBs	Cohort study (level 3b)	5 year patency	55/62 (89%) patent. 5 or these had mild narrowing.	CCB study is a sub-study of this paper and is underpowered to make firm conclusions
			Correlation with Calcium channel blocker usage	No correlation found between CCB usage and angiographic patency
Skubas et al, 2005, USA	30 patients receiving a radial artery as a T graft during CABG randomized to Normal Saline ( n=10) Nitroglycerin 0.5mcg/kg/min (n=10) Nicardipine 0.5mcg/kg/min (n=10) Then phenylephrine administered to assess level of induced vasospasm Radial arteries had papaverine infused intraluminally on harvest Transonic flowmeter used after separation from bypass to measure radial artery flow.	PRCT (Level 1b)	Flow on Administration of Phenylephrine	Normal Saline 40% ± 25% increase. Nitroglycerin 37% ± 27% increase. Nicardipine 48% ± 36% increase (P=0.533)	Study performed intra-operatively rather than post-operatively. Small study.
			Conclusions	Radial artery blood flow increases with vasoconstrictors with no evidence of vasospasm, either with or without CCBs or nitrates
Arena, 2002, Italy (translated)	50 patients undergoing CABG with radial artery randomized to 6 months of calcium channel blocker, nifedipine 40mg od ( N=26) No calcium channel blocker ( N=24) 32 patients then underwent angiography 16 to 24 months post-operatively	PRCT (Level 3b)	Angiographic findings	2 radial arteries occluded, due to progression of a plaque and competitive flow of native vessel. None deemed to be due to spasm. All other radial arteries patent.	Methods, Results, Statistics all poorly presented. No note of method of radial harvesting no patient demographics or tabulation of results.
Kalus et al, 2001, USA	Review of the literature searching Medline 1966-2000 for studies assessing the prevention of vasospasm of radial arteries using calcium channel antagonists and nitrates.	Systematic Review (Level 3a)	Key Findings	17 references found, All studies were either very small RCTs or cohort studies or in vitro studies. No clinical improvements in radial artery patency demonstrated in any of the reviewed papers.	Poor quality search of literature. No tabulation of results, or description of harvesting techniques.
Moran et al, 2001, Chile	115 patients receiving a radial arterial graft as part of a CABG procedure. Randomized to Diltiazem 1mcg/kg/min intraoperatively then 180mg/day for 1 year ( n=63 patients) No diltiazem ( n=53 patients) Angiography 1 year post-operatively	PRCT (level 1b)	Graft patency	Perfect patency 35/50 (69%). String sign 6/50 (12%). Occluded 10/50 ( 20%)	Exact patency results for those receiving Calcium channel blockers not described. Less than 50 % of patients underwent repeat angiography.
			CCB usage	No difference between CCB or no CCB groups
			Angina	96 % angina free at mean follow up of 30 months

Comment(s)

Gaudino[2005] randomized 100 consecutive patients who had radial artery grafts to Diltiazem or no therapy. All patients were evaluated clinically and with TI201 myocardial scintography but no differences were found. In addition 83 underwent angiography. Patency was over 95% in both groups and there was no difference between the groups. 12 patients had assessment of the vasospastic response of the radial artery to serotonin. Diltiazem did not attenuate this response. Gaudino[2001] also looked at the clinical and angiographic effects of chronic channel blocker therapy continued beyond the first year in those having radial artery grafts. 120 patients who had radial arteries with no evidence of radial artery dysfunction at 1 year were randomly assigned to continue therapy with diltiazem 120mg daily or suspend therapy. At 5 years there was no difference in angina recurrence(10% in both groups) radial territory ischaemia (~5% both groups) or angiographic patency(~95%) In the subgroup who underwent challenge with endovascular serotonin, the radial arteries underwent spastic contraction but there was again no significant difference between groups. Similar results were also published by this group in 1998 [Possati] and 2003[Possati]. Shapira compared the use of nitrates and calcium channel blockers in the prevention of radial artery spasm in a randomized trial. No differences in operative mortality or morbidity, long term patency, thallium stress testing, need for stenting, or myocardial infarction were found. In this American study the overall cost of treatment with diltiazem was much more expensive than with nitroglycerin ($16,340 v $1,096). Sperti evaluated the response to serotonin of the radial artery graft, the IMA graft and native coronary arteries in patients who had CABG with a radial artery graft. 22 patients were not on any calcium channel blockers and 9 were on chronic diltiazem treatment. Their results showed no significant difference in the diameter of the radial artery in its basal state between groups and thus oral diltiazem did not prevent serotonin induced vasoconstriction of the radial artery grafts. Acer followed 102 patients for 5 years who received a radial artery. All patients were started on diltiazem and converted to oral diltiazem 250 mg daily and oral aspirin 100 mg daily.50 patients had an angiogram. 64 radial grafts were studied and 83% were patent. Diltiazem had continued to be used in 27 and 23 were not on any treatment for various reasons. There were 8 graft failures in the CCB group and 4 in patients who had stopped CCBs. Broadman performed a prospective review of 175 of 249 patients. 2 patients had perioperative myocardial infarction but neither was related to radial artery dysfunction. Sixty patients underwent post operative angiography between 1 day and 40 weeks. Of these 28 were on calcium blocker therapy. Patency rate of the radial arteries was 95.7% and there was no effect with Calcium blocker usage. Possati[2003] followed up 90 patients who received a radial artery then an angiogram an average of 9 years post-operatively. All patients received Diltiazem for a year post-operatively but 51 patients stopped this medication for a variety of reasons after this. There was no difference in graft patency, which was still perfect in 88% of patients. Cameron performed an angiogram 5 years post radial artery grafting in 50 patients. 37 of these patients received calcium channel blockers. The patency rate was high at 89% and no correlation with CCB usage was found. Skubas randomized 30 patients receiving a radial artery. 10 had intravenous nitroglycerin, 10 had intravenous nicardipine and 10 had normal saline. An intraoperative flow probe assessed radial artery flow and then they measured the change in flow in response to a vasoconstrictor. The flow was similar for all groups and increased for all patients in response to a vasoconstrictor in response to a higher blood pressure. Thus no vasospasm was seen and a vasoconstrictor did not induce vasospasm. Arena performed angiography on 32 patients 1 year after radial artery harvest. Patients were randomized to nifedipine or control. There were only 2 patients whose radial arteries were found not to be patent and the reasons for this occlusion was felt to be technical rather then due to CCBs. In 2001 Kalus reviewed the literature for the use of Calcium channel blockers or nitrates for the prevention of vasospasm. They referenced 17 papers and summarized their findings in a descriptive fashion. They found only small RCTs, small cohort studies and in vitro studies, and concluded that all these studies consistently find no clinical benefits for calcium channel blockers. Moran et al randomized 115 patients receiving radial arteries to Diltiazem 180mg per day for 1 year or no treatment. Angiography at 1 year showed no difference and there were no clinical differences in symptoms or complications at 30 months follow up. Myers et al performed a survey of Canadian surgical centres. Of 27 responding centres, 25 centres routinely use calcium channel blockers and 12 use nitrates in addition to this.

Clinical Bottom Line

While routine use of Calcium channel blockers and nitrates in order to reduce vasospasm is in widespread use, none of the clinical studies that we identified provided any evidence for their benefit. Furthermore one study demonstrated that a vasoconstrictor mediated increase in blood pressure actually increased blood flow in the radial artery, and a further study reported that serotonin induced vasospasm was not attenuated by CCBs in vivo. All these studies are underpowered to exclude a benefit of vasodilators in improving graft patency in the medium term. However an RCT that sought to prove an increase of 5% in patency rates (which are already around 90% or more) with a power of 80% would have to recruit and perform medium term angiography on 948 patients.

References

1. Gaudino M, Luciani N, Nasso G, Salica A, Canosa C, Possati G. Is postoperative calcium channel blocker therapy needed in patients with radial artery grafts? J Thorac Cardiovasc Surg. 2005 Mar;129(3):532-5.
2. Gaudino M, Glieca F, Luciani N, Alessandrini F, Possati G. Clinical and angiographic effects of chronic calcium channel blocker therapy continued beyond first postoperative year in patients with radial artery grafts... Circulation. 2001 Sep 18;104(12 Suppl 1):I64-7.
3. Shapira OM, Alkon JD, Macron DS, Keaney JF Jr, Vita JA, Aldea GS, Shemin RJ. Nitroglycerin is preferable to diltiazem for prevention of coronary bypass conduit spasm. Ann Thorac Surg. 2000 Sep;70(3):883-8; discussion 888-9.
4. Sperti G, Manasse E, Kol A, Canosa C, Grego S, Milici C, Schiavello R, Possati GF, Crea F, Maseri A. Comparison of response to serotonin of radial artery grafts and internal mammary grafts to native coronary arteries and the effect of diltiazem. Am J Cardiol. 1999 Feb 15;83(4):592-6, A8.
5. Possati G, Gaudino M, Alessandrini F, Luciani N, Glieca F, Trani C, Cellini C, Canosa C, Di Sciascio G. Midterm clinical and angiographic results of radial artery grafts used for myocardial revascularization. J Thorac Cardiovasc Surg. 1998 Dec;116(6):1015-21.
6. Acar C, Ramsheyi A, Pagny JY, Jebara V, Barrier P, Fabiani JN, Deloche A, Guermonprez JL, Carpentier A. The radial artery for coronary artery bypass grafting: clinical and angiographic results at five years. J Thorac Cardiovasc Surg. 1998 Dec;116(6):981-9.
7. Brodman RF, Frame R, Camacho M, Hu E, Chen A, Hollinger I. Routine use of unilateral and bilateral radial arteries for coronary artery bypass graft surgery. J Am Coll Cardiol. 1996 Oct;28(4):959-63.
8. Myers MG, Fremes SE. Prevention of radial artery graft spasm: a survey of Canadian surgical centres. Canadian Journal of Cardiology, 2003:19(6);677-681.
9. Possati G, Gaudino M,Prati F, Alessandrini F, Trani C, Glieca F, Mazzari MA, Luciani N, Schiavoni G. Long-Term Results of the Radial Artery Used for Myocardial Revascularization. Circulation, 2003;108:1350-1354.
10. Cameron J, Trivedi S,Stafford G,Bett N. Five-year Angiographic Patency of Radial Artery Bypass Grafts. Circulation, 2004;110[suppl II]:II-23-II-26.
11. Skubas N, Barner HB, Apostolidou I, Lappas G. Phenylephrine to increase blood flow in the radial artery used as a coronary bypass conduit. Journal of Thoracic and Cardiovascular Surgery, 2005;130930:687-692.
12. Arena G, Abbate M. Is calcium antagonist administration necessary after aortocoronary bypass with the radial artery? Italian Heart Journal Supplement, 2000;1(2):256-8.
13. Kalus JS, Lober CA. Calcium-channel antagonists and nitrates in coronary artery bypass patients receiving radial artery grafts. Annals of Pharmacotherapy, 2001;35(5):631-635.
14. Moran SV, Baeza R, Guarda E, Zalaquett R, Irarrazaval J, Marchant E, Deck C. Predictors of Radial Artery Patency for Coronary Bypass Operations. Ann Thorac Surg 2001; 72:1552–1556.