Predictive Value of Post-Percutaneous Coronary Intervention Quantitative Flow Ratio for Vessel-Oriented Composite Endpoint

At present, there is a lack of indicators, which can accurately predict the post-percutaneous coronary intervention (post-PCI) vessel-oriented composite endpoint (VOCE). Recent studies showed that the post-PCI quantitative flow ratio (QFR) can predict post-PCI VOCE. PubMed, Embase, and Cochrane were searched from inception to March 27, 2022, and the cohort studies about that the post-PCI QFR predicts post-PCI VOCE were screened. Meta-analysis was performed, including 6 studies involving 4518 target vessels. The results of the studies included in this meta-analysis all showed that low post-PCI QFR was an independent risk factor for post-PCI VOCE after adjusting for other factors, HR (95% CI) ranging from 2.718 (1.347–5.486) to 6.53 (2.70–15.8). Our meta-analysis showed that the risk of post-PCI VOCE was significantly higher in the lower post-PCI QFR group than in the higher post-PCI QFR group (HR: 4.14, 95% CI: 3.00–5.70, P < 0.001, I2 = 27.9%). Post-PCI QFR has a good predictive value for post-PCI VOCE. Trial Registration. This trial is registered with CRD42022322001.


Introduction
Coronary atherosclerotic heart disease (CHD) is one of the most common cardiovascular diseases in clinical practice.Medication and percutaneous coronary intervention (PCI) can relieve symptoms and improve outcome in patients with CHD.However, some patients may still experience vesseloriented composite endpoint (VOCE), defned as the composite of vessel-related cardiac death, vessel-related myocardial infarction, and target vessel revascularization.Te incidence of post-PCI VOCE was about 7% [1,2].Previous studies have shown that intravascular ultrasound (IVUS), optical coherence tomography (OCT), and fractional fow reserve (FFR) can predict the long-term prognosis of the post-PCI patients [3][4][5][6][7][8][9][10].However, these methods exert some limitations, such as invasive, high cost, and complex operation.Terefore, fnding a simple method that can accurately predict the long-term prognosis of the post-PCI patients is crucial.
In 2015, Tu [11] proposed a quantitative fow ratio (QFR) based on FFR, a noninvasive and guidewire-free FFR rapid analysis system.Te QFR combines a three-dimensional reconstruction technology of coronary angiography, a hemodynamic system, and artifcial intelligence with respect to blood fow quantifcation to accurately evaluate the physiological function of the coronary artery.
Recently, some studies have shown that post-PCI QFR can predict post-PCI VOCE [1, [12][13][14][15][16][17][18][19].Among them, the results of 6 cohort studies showed that the risk of post-PCI VOCE was higher in the group with lower post-PCI QFR than in the group with higher post-PCI QFR [1, [12][13][14][15][16].However, the population and sample size of these 6 cohort studies were not exactly the same, and there were diferences in hazard ratio (HR) values and 95% confdence interval (95% CI).Terefore, we conducted this meta-analysis to obtain the cumulative sample size and improve the statistical efciency.

Inclusion Criteria and Exclusion
Criteria.Te inclusion criteria were as follows: (1) cohort study; (2) the study subjects were post-PCI CHD patients; (3) QFR of the target vessels was measured after successful PCI; (4) according to the post-PCI QFR, the target vessels of all patients together were divided into two cohorts: lower post-PCI QFR group and higher post-PCI QFR group.(5) Te primary endpoint of the study was post-PCI VOCE.(6) Cox regression was used for multiple-variable analysis.(7) After adjusting for other infuencing factors, post-PCI QFR was analyzed as an independent risk factor for post-PCI VOCE.
Case-control studies were cross-sectional and timeindependent, in which odd ratio (OR) was generally used for statistical description.Outcome measures of cohort studies were time-dependent, in which hazard ratio (HR) was generally used for statistical description.It was not appropriate to put OR and HR together for statistical merging, and case-control studies had a lower level of evidence-based medical evidence than cohort studies.Terefore, we excluded 3 case-control studies [17][18][19].

Data Extraction.
Te data, such as author, year of publication, country, data source, follow-up time, number of cases, number of target vessels, age, the proportion of males, proportion of hypertension, proportion of diabetes, proportion of smoking, the proportion of hyperlipidemia, left ventricular ejection fraction, proportion of target vessels, PCI type, post-PCI QFR cutof value, hazard ratio (HR), 95% confdence interval (95% CI), and number of post-PCI VOCE, were independently extracted by two researchers from the fnally included studies.Te risk of bias was independently assessed by two researchers according to the PRISMA statement.Te disagreements were resolved by discussion.

Statistical Analysis.
Meta-analysis was performed using Stata 17 software.Heterogeneity was evaluated using Cochran Q test and I 2 test.I 2 > 50% was considered evident heterogeneity.We used the random-efects model for all metaanalysis.Publication bias was assessed by funnel plots and Egger's test.P < 0.05 was considered statistically signifcant.

Results
A total of 203 articles were retrieved: 82 from PubMed, 78 from Embase database, 41 from Cochrane database, and 2 from manual search.After these articles were imported into NoteExpress reference management software (https://www.inoteexpress.com/aegean/),61 duplicates, 12 reviews, 2 meta-analysis, and systematic reviews were excluded.After reading the abstract of the remaining 128 articles, 115 articles were further excluded.After reading the full text of the remaining 13 articles, 6 articles were fnally included in this meta-analysis [1, [12][13][14][15][16]. Te fowchart of literature screening is shown in Figure 1.
Te quality of the included studies was evaluated according to the Newcastle-Ottawa scale (NOS), Table 2. Five studies were of high quality with scores of 8 or 9, and one study was of general quality with a score of 6.
Te post-PCI QFR cutof value was not completely same, which ranged from 0.89 to 0.94, Table 3. Te target vessel numbers in lower post-PCI QFR group and higher post-PCI QFR group were 1019 and 3499, respectively.Te post-PCI VOCE numbers in lower post-PCI QFR group and higher post-PCI QFR group were 168 (16.49%) and 105 (3.00%), respectively.Te results of the studies included in this metaanalysis all showed that low post-PCI QFR was an independent risk factor for post-PCI VOCE after adjusting for other factors, HR (95% CI) ranging from 2.718 (1.347-5.486) to 6.53 Our meta-analysis showed that the risk of post-PCI VOCE was signifcantly higher in the lower post-PCI QFR group than in the higher post-PCI QFR group (HR: 4.14, 95% CI: 3.00-5.70,P < 0.001, I 2 � 27.9%; Figure 2).Funnel plots were almost symmetric, indicating that there was no evident publication bias, Figure 3. Egger's test also showed no publication bias (P � 0.804).

Discussion
Since Pijls et al. [20] proposed FFR in 1993, it had become the gold standard for functional evaluation of coronary artery stenosis after long-term basic and clinical research [21].It involves sending a guidewire with a pressure sensor to the distal end of the coronary artery and measuring the ratio of the pressure at the distal end to the pressure at the proximal end.It requires the use of adenosine, which some patients are intolerant of.Terefore, Tu [11] proposed QFR in 2015, which involves reconstructing the threedimensional model of the coronary artery and calculating the process of blood fow pressure changes in the whole vessel according to the coronary angiography image.QFR does not require the use of drugs and does not require the use of guidewire.Compared with FFR, QFR has the advantages of simpler operation and better security.Both FFR and QFR belong to functional indicators, which can more accurately refect the impact of lesions on cardiac function than the pure degree of vascular stenosis.FFR is a direct measurement of pressure and can only be performed during the operation.As long as there is past or present coronary angiography image, QFR can be performed at any time.Terefore, post-PCI QFR can be calculated based on post-PCI coronary angiography images from past prospective databases, and the relationship between post-PCI QFR and long-term prognosis of patients can be analyzed.In this meta-analysis, fve studies were retrospective analyses of previous prospective data [12][13][14][15][16], and the other one was a prospective clinical trial [1].
2014 ESC/EACTS Guidelines had clearly stated that it was benefcial to guide PCI based on FFR values measured before PCI [21].In recent years, studies had shown that QFR and FFR had a very high diagnostic consistency [22,23].It was also benefcial to guide PCI based on the QFR values measured before PCI [24].In addition, it was found that FFR values measured after PCI could predict the long-term outcome of patients [25].Systematic reviews and metaanalysis had also reached similar conclusions [10,26].In recent years, studies had shown that QFR could also predict post-PCI VOCE [1, [12][13][14][15][16].However, there has been no relevant systematic review and meta-analysis.Terefore, we conducted this meta-analysis, and the results showed that the hazard ratio of post-PCI VOCE was signifcantly higher in the lower post-PCI QFR group than in the higher post-PCI QFR group.
After successful PCI, many patients still had residual disease, stent underexpansion, and stent edge dissection, which were very important reasons for the occurrence of post-PCI VOCE.Post-PCI QFR measured the stenosis function of target vessels after PCI, which could refect not only the stented segment but also the nonstented segment.Biscaglia et al.'s [1] study showed that 13% of suboptimal post-PCI QFR was due to PCI segments.For these patients with suboptimal post-PCI QFR, further stent optimization during PCI might could reduce the occurrence of post-PCI VOCE.Tis meta-analysis showed that mean or median of QFR after angiographically successful PCI were higher than 0.9, and that post-PCI QFR of 5.9% to 7.4% target vessels were still lower than 0.8.Post-PCI QFR could help identify patients at high risk for post-PCI VOCE.In addition, it was noteworthy whether the suboptimal QFR was derived from the PCI segment.
In all 6 studies included in this meta-analysis, post-PCI QFR was used as a binary variable for Cox regression

4
Journal of Interventional Cardiology    Although the heterogeneity of this meta-analysis was not evident, we still conducted subgroup analyses.Te results of subgroup analyses showed that we might need to pay more attention to those who underwent DCB than to those who underwent DES.We might need to pay more attention to the period of post-PCI 1 year than post-PCI 2 year.Biscaglia et al.'s [1] study seems to focus on European participants.Kogame [12] study seems to have diverse ethnical backgrounds.Tang et al.'s [13], Tang's [14], Liu and Ding's [15] and Zhang [16] studies seem to focus on Chinese participants.Post-PCI QFR might have a better predictive value for post-PCI VOCE in Chinese population than other populations.Genetical and cultural implication may be one of the reasons for the diference between Chinese population and other populations.Further investigations are needed to fnd the pathological cause.

Limitations
Tere were some limitations to this meta-analysis.Data recording might be subject to bias, because data of some included studies was from previously unregistered database.
In the studies included in this meta-analysis, follow-up time, PCI types, post-PCI QFR cutof values, and adjusted factors were not completely consistent, which might afect the results of this meta-analysis to some extent.Our meta-analysis would be more convincing if we could obtain the raw data of all studies included in our meta-analysis, reanalyze them, and obtain an optimal cutof value for post-PCI QFR.To some extent correlation among vessels in a patient may afect results.However, the purpose of our study is to study the predictive value of post-PCI QFR for post-PCI VOCE.Both subjects (post-PCI QFR) and outcomes (post-PCI VOCE) were analyzed based on the number of vessels.Tis method should be feasible.Tis is also the case with other metaanalysis, such as the meta-analysis published by Hwang [26] in JAMA in 2022.Hence, the results of this study should be considered exploratory.

Conclusion
In summary, this meta-analysis showed that post-PCI QFR had a good predictive value for post-PCI VOCE.Large sample prospective studies with carefully controlling for confounders are needed to confrm this conclusion.

0633 Figure 2 :
Figure 2: Forest plot (meta-analysis of the hazard ratio of post-PCI VOCE in the lower post-PCI QFR group than in the higher post-PCI QFR group).

Figure 3 :
Figure 3: Funnel plots (the hazard ratio of post-PCI VOCE in the lower post-PCI QFR group than in the higher post-PCI QFR group).

Table 2 :
Quality evaluation of included studies (the Newcastle-Ottawa scale, NOS).