Written by Aaysha Cader, MD, MRCP and Saidur Rahman Khan, MD, PhD
Ibrahim Cardiac Hospital & Research Institute, Dhaka, Bangladesh
Transradial access (TRA) is gaining increasing popularity for diagnostic and therapeutic interventions globally. Radial Artery Occlusion (RAO) however, is the most frequent complication of transradial access. An occluded radial artery precludes its future use for future catheterization procedures, as a conduit in coronary artery bypass grafting or for arteriovenous fistula creation.1
A number of randomized controlled trials have tested different strategies to reduce RAO, particularly in recent times. Vasodilators such as nitroglycerin have been used prophylactically to reduce radial artery spasms. By virtue of their anti-inflammatory effects and reduction of intimal hyperplasia, they could also enhance regional arterial flow, facilitating patent hemostasis.
A previous randomized trial of intraarterial nitroglycerin vs placebo given through the sheath at the end of the procedure showed a reduction of RAO at 24 hours.2 In the PATENS trial, the investigators used an interesting 2×2 factorial design to evaluate whether nitroglycerin administration either at the beginning or at the end of a TRA procedure, might prevent RAO.3
This trial, recently and published in JACC: Cardiovascular Interventions, was a multicentre, randomized, double-blind, 2-by-2 factorial design trial of all-comer patients undergoing TRA for either diagnostic or therapeutic coronary intervention via either 5 or 6 French sheaths. The trial compared the superiority of 500 µg nitroglycerin (intervention) versus placebo. The 2-by-2 factorial design entailed that the patient be randomized at two-time points:
- early: immediately after access was obtained and upon sheath insertion; and once again
- late: after completion of the procedure and just before sheath removal.
Intra-arterial heparin (5,000 U) was given through the radial sheath to all patients. In cases of PCI, additional heparin was used (total 100 IU/kg). Minimal pressure patent arterial hemostasis was achieved by a pneumatic compression device.
The primary outcome was early RAO (at 24 hours): This was evaluated by duplex Doppler Ultrasound (DUS) within 24 hours of removal of the compression device by operators who were blinded to the randomization allocation.
The secondary outcome was late RAO, which was assessed at 30 days by DUS for recanalization among all those patients with early RAO.
The study was powered at 80% to test superiority for the primary endpoint with an estimated 40% reduction of RAO incidence for the intervention, at a significance level of 5%, with an expected incidence of 7.7% of early RAO in the comparator arm. A possible 0.3 interaction was anticipated considering factorial design. The sample size was estimated at 2,040. Accordingly, 2,040 patients underwent transradial catheterization at 3 centers in Brazil, 1020 in each arm at each randomization. The mean age was 61.7 years; 37.9% were women. 75.2% of procedures were diagnostic coronary angiographies. 25.6% of patients had prior radial catheterization. 60.6% had 5 F radial sheaths, while 39.4% had 6 F sheaths.
There were no significant differences in the primary outcome, RAO at 24 hours between nitroglycerin early use and placebo (2.5% vs 2.3%; P = 0.664); RAO was also not different between nitroglycerin late use and placebo (2.3% vs 2.5%; P = 0.664). Furthermore, a preliminary test for interaction among the factors showed no statistical significance (P = 0.665). In the multi-arm analysis, the combined use of nitroglycerin, early and late, did not show benefit compared with placebo at either of the time points examined.
Although not reaching statistical significance, numerically more radial artery spasm was noted among those who did not receive nitroglycerin pre-procedure (early group): 13.4% vs 10.8% (p=0.06). Needless to say, caution must be exercised when interpreting such ‘trends’.
At 30-day follow-up, recanalization by the antegrade flow on DUS was 30.6%, with no difference between groups. Subgroup analysis showed no benefit from nitroglycerin use in any of the evaluated subgroups, which included sex, age, operator experience, procedure type, sheath size, sheath to artery ratio, and spasm. It has not been mentioned if these subgroups were pre-specified.
Among the 24.8% of patients who underwent PCI (11.6% elective, 13.2% ad hoc), only 1.8% had RAO, with no significant difference with nitroglycerin use compared with placebo at either of the 2-time points.
The presence of clinical spasm (OR: 3.53; 95% CI: 1.87-6.66; P < 0.001) and access achieved with more than a single puncture attempt (OR: 2.58; 95% CI: 1.43-4.66; P = 0.002) were significant independent predictors of 24-hour RAO by multivariable logistic regression analysis.
Overall, the results of this factorial design trial indicate that the intraarterial use of nitroglycerin given before or after puncture does not reduce the risk of early RAO after TRA. The investigators included an all-comer population, of whom 24.8% underwent PCI, including ad hoc PCI, lending greater generalizability to the findings. Also, both 5 and 6 F sheaths were allowed, although the majority were indeed 5 F.
Two prior randomized trials have investigated the impact of nitroglycerin in RAO. Dharma et al, randomized 1704 patients 1:1 in 3 global centers to receive either 500µg intra-arterial nitroglycerin or placebo at the end of the radial procedure and before sheath removal. 2 Nitroglycerin reduced the risk of RAO at 24 hours, as compared with placebo (8.3% vs. 11.7%; odds ratio, 0.62; 95% confidence interval (CI), 0.44–0.87; P=0.006).2
In a smaller RCT, Chen et al. randomized 188 patients to receive subcutaneous injection of 0.5 mL 0.1% nitroglycerin or a placebo prior to sheath insertion.4 After sheath insertion, the subjects received an intra-arterial injection of 200 µg nitroglycerin and 3000 IU unfractionated heparin. RAO was substantially lower in the nitroglycerin-treated group versus placebo (5.4% versus 14.4%; P=0.04).
In comparison to both of these trials, very low levels of RAO were recorded in both groups in the PATENS trial, which could be partially explained by the application of contemporary best practices for RAO prevention.1 These include patent hemostasis, the use of intra-arterial heparin in higher doses (5000 U), and potentially, more increased anticoagulation among the PCI (24.8%) patients. Neither of the previous trials mentions a patent hemostasis protocol in their methods,2,4, and indeed the use of a patent hemostasis protocol may have taken away the RAO-prevention advantage of nitroglycerin by improving regional flow.
The percentage of women enrolled in this trial was 37.9%. Particularly as female sex is a risk factor for RAO,1 they should also be enrolled in greater proportions. Furthermore, a pre-procedural DUS with measurements of radial artery diameters may have allowed for further analyses of predictors of RAO and spasm and assessment of nitrates response according to baseline radial artery diameters. Reporting of radial artery spasms in all trials assessing RAO, may also be a useful factor when interpreting trial findings.
So, what are the implications of this trial in clinical practice? In many parts of the world, best practice for RAO prevention is not entirely adhered to, particularly patent hemostasis, and thus, there may still be a role for nitroglycerin role for nitroglycerin in RAO prevention. Also, the fact that spasm was numerically lower in those who received nitroglycerin pre-procedure and that spasm was indeed an independent predictor of RAO is additional food for thought. Furthermore, this trial only looked at the effect of nitroglycerin: there remains scope for randomized evidence in the use of other spasmolytics (e.g. verapamil and diltiazem) as both a strategy to reduce RAO, and to prevent spasms. And finally, any future RAO trial design and planning should also account for the low incidence of RAO in presence of contemporary best-practice.
- Bernat I, Aminian A, Pancholy S, Mamas M, Gaudino M, Nolan J, et al; RAO International Group. Best Practices for the Prevention of Radial Artery Occlusion After Transradial Diagnostic Angiography and Intervention: An International Consensus Paper. JACC Cardiovasc Interv. 2019;12(22):2235-2246.
- Dharma S, Kedev S, Patel T, Kiemeneij F, Gilchrist IC. A novel approach to reduce radial artery occlusion after transradial catheterization: postprocedural/ prehemostasis intra-arterial nitroglycerin. Catheter Cardiovasc Interv. 2015;85:818–825.
- da Silva RL, de Andrade PB, Dangas G, Joaquim RM, da Silva TRW, Vieira RG, et al. Randomized clinical trial on prevention of radial occlusion after transradial access using nitroglycerin (PATENS trial). J Am Coll Cardiol Intv. 2022,00(00):000-000.
- Chen Y, Ke Z, Xiao J, et al. Subcutaneous injection of nitroglycerin at the radial artery puncture site reduces the risk of early radial artery occlusion after transradial coronary catheterization. Circ Cardiovasc Interv. 2018;11(7):e006571.
Aaysha Cader, MD, MRCP is an Assistant Professor of Cardiology at Ibrahim Cardiac Hospital & Research Institute, Dhaka, and is currently pursuing a part-time MSc in Clinical trials at the University of Oxford. She has a special interest in interventional cardiology, acute coronary syndromes, and heart disease in women. She is a World Heart Federation Emerging Leader and a co-founder of the Global Women in Cardiology (WIC) – Early Career collaboration. You can follow her on twitter: @aayshacader