Remote Postconditioning Fails to Reduce Myocardial Injury in Non-urgent PCI Patients

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In elective patients, remote ischemic conditioning during percutaneous coronary intervention (PCI) does not decrease periprocedural myocardial injury, according to a randomized trial published online April 1, 2014, ahead of print in Circulation: Cardiovascular Interventions. Moreover, it makes no difference whether the remote conditioning is performed in the arm or the thigh.

Selected data from the Remote Ischemic Postconditioining-Percutaneous Coronary Intervention randomized trial were first presented March 29, 2014, at the American College of Cardiology/i2 Scientific Session in Washington, DC.

Investigators led by Shahar Lavi, MD, of the University of Western Ontario (London, Canada), randomized 360 patients with stable or unstable (28%) angina and negative baseline troponin T levels undergoing PCI equally to remote ischemic postconditioning of the arm (n = 120) or thigh (n = 120) or sham postconditioning (placebo; n = 120).

Ischemic postconditioning consisted of 3 cycles of blood pressure cuff inflation (to ≥ 200 mm Hg [recommended 300 mm Hg in the thigh group] and > 50 mm Hg above systolic pressure) for 5 minutes (ischemia) followed by 5 minutes of deflation (reperfusion), immediately after stent deployment.

No Difference in Endpoint Enzyme Elevations

After the procedure, troponin levels were elevated above the upper limit of normal (ULN) in 60% of all patients. The proportion of patients with troponin T levels greater than 3 times the upper limit of normal (primary endpoint) was similar for all 3 groups, as were troponin T levels in the MI range (> 5xULN). In addition, there were no differences in acute kidney injury (AKI) within 24 hours or  elevation of high-sensitivity C-reactive protein (hs-CRP) above baseline among the groups (table 1).

Table 1. Laboratory Parameters

 

Arm
(n = 120)

Thigh
(n = 120)

Control
(n = 120)

P Value

Primary Endpoint

30%

35%

35%

0.64

Troponin > 5xULN

22%

24%

25%

0.82

AKI Within 24 Hr

4%

8%

6%

0.55

hs-CRP, µmol/L
Baseline
8-24 Hr

 
4.2 ± 5.6
5.7 ± 7.4

 
3.5 ± 4.6
4.8 ± 5.3

 
3.6 ± 4.6
4.7 ± 5.3

 
0.46
0.40


In a subanalysis of patients 65 years or younger (n = 196), the primary endpoint occurred in 21% of the arm group, 32% of the thigh group, and 36% of the control group (P = 0.13) with an advantage for the arm group vs the control group (P = 0.04). There was no evidence of a treatment effect due to age (P for interaction = 0.11), sex (P for interaction = 0.11), or presence of unstable angina (P for interaction = 0.94).

On multivariable adjustment, only use of rotational atherectomy (P = 0.02) and stent length (P = 0.004) were predictors of outcomes.

Despite the negative findings, the authors conclude that “[t]he preferred mode of applying ischemic conditioning, number of cycles, and timing should be further explored.”

Defining the Limits of Conditioning

The prospects for a cardioprotective benefit in elective patients may have been slim from the outset, but “to look at it positively, this study at least sets the limits of conditioning,” Karin Przyklenk, PhD, of Wayne State University School of Medicine (Detroit, MI), told TCTMD in a telephone interview. “Is it just for STEMI and surgical patients, where there is an excellent to very good chance of having enzyme release, or is there a broader application? I think [these data] help define the patient population where conditioning might be useful.”

Dr. Przyklenk praised the investigators for addressing the question of whether the magnitude of conditioning is larger in the leg compared with the arm. “It makes inherent sense that the more muscle that is rendered ischemic during the trigger for remote conditioning, potentially the better the outcome,” she said. The fact that no differential effect was seen here may simply be due to the patient population, which would be expected to have only a modest enzyme release, she commented.

The same explanation holds true for the absence of a benefit specifically in unstable angina patients, she observed, adding that thanks to their condition, some may have in effect “preconditioned themselves.”

Factors That May Have Hindered Benefit

Importantly, Dr. Przyklenk said, the experimental literature suggests that starting the conditioning stimulus when the first stent is deployed is already too late, especially since the time required for release of conditioning factors from the ischemic limb is unknown. “The other issue,” she added, “is that… if there is any sort of TIMI flow during the occlusion, or if the region at risk is small because of collateral flow, then conditioning is essentially ineffective. And it is unlikely that these patients had a fully blocked TIMI 0 bed.”

In sum, she said, “It could be that all 3 of these factors—the patient population, the flow status, and the timing—are all conspiring against a positive outcome.”

Dr. Przyklenk also noted that the gold standard endpoint of conditioning studies has been infarct size. That can be difficult to assess in clinical trials, she acknowledged, “but as a first pass I would have liked to have seen [more firm] data on the enzyme release over time and areas under the curve rather than just a cutoff [of more than 3 times the upper limit of normal] at some pretty selective time points.”

Finally, both the authors and Dr. Przyklenk pointed to a procedural factor that may have helped undermine efficacy. The opioid fentanyl was used to keep patients comfortable during BP cuff inflations, and opioid receptor signaling is one of the proposed mechanisms of conditioning, she explained, “So you’ve already essentially delivered that [conditioning] signal pharmacologically.” Also, she noted, pain—blunted by the fentanyl—may be an important component of cardioprotection.

Study Details

Baseline characteristics were similar across groups. Overall, 27% were women, 31% had diabetes, and 42% had a previous MI. Bivalirudin was used in 58% of patients, while glycoprotein IIb/IIIa inhibitors were used in conjunction with unfractionated heparin in 25%; the remainder received unfractionated heparin alone. Rotational atherectomy was used less often in the thigh group than either the arm or control group (P = 0.01). All other procedural characteristics were comparable among the 3 groups. 

An effort was made to keep both patients and operators as blinded as possible to the conditioning. Troponin was measured at 6, 18, and 24 hours postprocedure, with the highest level used for outcome assessment.

 


Source:
Lavi S, D’Alfonso S, Diamantouros P, et al. Remote ischemic postconditioning during percutaneous coronary interventions: Remote Ischemic Postconditioning-Percutaneous Coronary Intervention randomized trial. Circ Cardiovasc Interv. 2014;Epub ahead of print.

 

 

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Remote Postconditioning Fails to Reduce Myocardial Injury in Non-urgent PCI Patients

In elective patients, remote ischemic conditioning during percutaneous coronary intervention (PCI) does not decrease periprocedural myocardial injury, according to a randomized trial published online April 1, 2014, ahead of print in Circulation Cardiovascular Interventions. Moreover, it makes no difference whether the
Disclosures
  • The study was supported by The Heart and Stroke Foundation of Canada; The Academic Development Fund, Western University; and Lawson Health Research Institute.
  • Dr. Lavi reports no relevant conflicts of interest.
  • Dr. Przyklenk reports serving on the scientific advisory board of Infarct Reduction Technologies.

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