Clinical value of fractional flow reserve in coronary heart disease: A retrospective study

Abstract

This study investigated the clinical value of coronary arteriography (CAG) combined with fractional flow reserve (FFR) in the treatment of coronary heart disease (CHD) with coronary artery stenosis exceeding 70%. A retrospective analysis was conducted on 344 patients with CHD treated at the Gansu Institute of Cardiovascular Science from January 2020 to May 2022. The patients were divided into the CAG group (n = 138) and the CAG + FFR group (n = 206). Among these patients, those with coronary artery stenosis exceeding 70% underwent an FFR functional examination to accurately determine indicators for coronary intervention. The data collected included demographic information, number of stents, number of vascular lesions, treatment methods, and the occurrence of major adverse cardiovascular events (MACE) at the 6-month follow-up. No significant differences were found between the 2 groups in terms of age, gender, underlying diseases, body mass index (BMI), smoking history, and blood lipid profile. The rate of surgical treatment in the CAG group and the CAG + FFR group was 88.41% and 43.69%, respectively. The CAG + FFR group showed a 44.72% reduction in the need for surgical treatment and a reduced number of stents placed, which helped prevent overtreatment. Additionally, there was no statistical difference between the 2 groups in MACE such as angina pectoris, myocardial infarction, and sudden cardiac death at the 6-month follow-up. After combined CAG examination with FFR measurement, the number of CHD patients with coronary artery stenosis exceeding 70% requiring surgical intervention decreased by 44.72%. FFR could significantly prevent overtreatment and provide more precise guidance for CHD treatments.

1. Introduction

Cardiovascular diseases have the highest morbidity and mortality worldwide, leading to more than 17.5 million deaths annually and projected to increase to 23.6 million by 2030.^[1,2] Ischemic heart disease, caused by coronary circulation disorders, is the most common cause of death.^[3] Coronary arteriography (CAG) is a commonly used and effective method for diagnosing coronary heart disease (CHD). However, relying solely on CAG for the assessment of stenosis degree is considered unreliable in determining the indications for percutaneous coronary intervention (PCI).^[4] Based on multi-center evidence-based medicine, the European guidelines for interventional therapy of CHD recommend functional assessment of coronary artery disease and guiding revascularization using fractional flow reserve (FFR) in patients with stable CHD.^[5]

FFR is defined as the ratio between the maximum achievable blood flow in a diseased coronary artery and the theoretical maximum flow in a normal coronary artery.^[6] Long-term basic and clinical research has revealed that CAG alone is limited to providing an anatomical assessment of stenosis, without being able to functionally evaluate its impact on distal blood flow.^[7] In other words, the morphologic CAG method is incapable of identifying the extent of myocardial ischemia, which may lead to an overestimation or underestimation of the severity of the lesion, consequently resulting in overtreatment or undertreatment. With the development of FFR over the past 2 decades, it is widely acknowledged that for moderately stenotic lesions, especially those in the proximal anterior descending artery, revascularization can be delayed if FFR > 0.8, should be performed if FFR < 0.75, and is most beneficial if FFR is between 0.75 and 0.8.^[8]

This study aims to assess the clinical significance of CAG combined with FFR for the treatment of CHD with coronary artery stenosis exceeding 70%. The findings on FFR-guided coronary intervention were presented. We found that the combination of CAG and FFR could decrease the number of CHD patients requiring surgical intervention. Our findings may help prevent overtreatment while providing more accurate treatment guidance for CHD patients.

2. Materials and methods

2.1. Study population

A total of 344 inpatients diagnosed with CHD at the Gansu Institute of Cardiovascular Science between January 2020 and May 2022 were included in this study. The inclusion criteria were: Patients with a confirmed clinical diagnosis of CHD; Patients with coronary artery stenosis >70%, as confirmed by CAG; Patients who underwent FFR to determine the necessity of interventional therapy; Patients aged 18 years old and older; and Patients with good compliance and complete clinical and follow-up data. Patients were excluded if they had: a history of acute myocardial infarction within the past month; New York Heart Association functional classification of grade III or higher; left ventricular ejection fraction <30%; a life expectancy of <1 year; contraindications to the treatments involved in the study; abnormal coagulation function; or, severe dysfunction of other organ systems. This study protocol was in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Lanzhou First People’s Hospital (Approval No.: 2024A-6). All participants signed the written informed consent.

2.2. Coronary arteriography

Before CAG, patients routinely received aspirin and statins, or a combination of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and β-blockers. Under the cardiovascular imaging system, catheterization was performed through the radial artery or femoral artery. The Judkins angiographic catheter was used for multiple-angle imaging and the dynamic images were recorded.

2.3. FFR measurement

FFR was measured for all patients diagnosed with coronary artery stenosis exceeding 70% based on CAG results. This decision was made to provide insights into the functional significance of lesions across a spectrum of coronary artery disease. While European Society of Cardiology (ESC) guidelines recommend FFR measurement primarily for lesions deemed moderate (40% to 70% stenosis), we intended to explore the potential of FFR to assist in decision-making for all patients with significant stenosis, especially given the nuances and individual patient factors that may influence treatment decisions. Briefly, FFR was measured using an invasive pressure transducer pressure wire (Model: C12059, St. Jude Medical, Inc., St. Paul). Adenosine triphosphate at a dosage of 140 μg/(kg min) was intravenously injected through the median cubital vein. The retraction technique was used for diffuse and multiple lesions to identify the culprit lesions.

2.4. Treatment

For patients without evidence of ischemia, PCI with stents or off-pump coronary artery bypass (OPCAB) was performed based on the FFR results. Following the procedure, a daily regimen of oral aspirin at 100 mg in combination with clopidogrel bisulfate at 75 mg, or ticagrelor at 180 mg, was administered continuously for 1 year.

2.5. Grouping

Patients were assigned to either the CAG group (n = 138) or the CAG combined FFR (CAG + FFR) group (n = 206). Patients in the CAG group underwent PCI or OPCAB for coronary artery stenosis of 75% or more, while those in the CAG + FFR group received PCI or OPCAB for coronary artery stenosis of more than 70% and FFR >0.8 (i.e., positive).

2.6. Data collection

Patient data were collected, including age, gender, smoking history, body mass index (BMI), underlying diseases, and blood lipid profile. Moreover, clinical information such as surgical approach, lesion sites, and the number of stents was recorded.

2.7. Follow-up

Follow-up was conducted 6 months after treatment, through both regular outpatient and telephone follow-up. The outpatient follow-up involved routine examinations of electrocardiogram, liver and kidney function, electrolyte levels, blood lipid profile, glycosylated hemoglobin, blood routine, and cardiac ultrasound. The telephone follow-up focused on monitoring for major adverse cardiovascular events (MACE), including angina pectoris, myocardial infarction, and sudden cardiac death, over 6 months.

2.8. Outcome measurement

The primary outcome was the rate of surgical treatment, while the secondary outcome was the occurrence of MACE.

2.9. Statistical analysis

In the study, continuous variables are presented as mean ± standard deviation, while categorical variables are expressed as n (%). The chi-square test was used to compare the categorical variables, and the t-test was used for the analysis of continuous variables. Statistical significance was set at P = .05. All statistical analyses were performed using SPSS, Version 22.0 (SPSS Inc., Chicago, IL, USA).

3. Results

3.1. Baseline data

The general clinical characteristics of the 2 groups are presented in Table 1. Among the 138 patients in the CAG group, 76 (55.07%) were male and 62 (44.93%) were female, with an average age of 62.78 ± 8.79 years. In the CAG + FFR group, which consisted of 206 patients, 127 (61.65%) were male, and 79 (38.35%) were female, with an average age of 63.41 ± 6.79 years. The mean BMI was 26.51 ± 4.88 for the CAG group and 26.34 ± 4.37 for the CAG + FFR group. Additionally, there were 56 (40.58%) cases of diabetes and 61 (44.20%) cases of hypertension in the CAG group, and 81 (39.32%) cases of diabetes and 97 (47.09%) cases of hypertension in the CAG + FFR group. Furthermore, 58 (48.03%) and 95 (46.12%) patients had a history of smoking in the CAG group and the CAG + FFR group, respectively. No significant differences were observed between the 2 groups in blood lipid profile, such as total cholesterol, triglyceride, high-density lipoprotein, and low-density lipoprotein cholesterol (P > .05).

Table 1.

Comparison of demographic characteristics between the 2 groups.

	CAG group (n = 138)	CAG + FFR group (n = 206)	P value
Gender
Male	76 (55.07%)	127 (61.65%)	.431
Female	62 (44.93%)	79 (38.35%)
Age	62.78 ± 8.79	63.41 ± 6.79	.589
Underlying disease
Hypertension	61 (44.20%)	97 (47.09%)	.571
Type 2 diabetes	56 (40.58%)	81 (39.32%)	.432
BMI (kg/m2)	26.51 ± 4.88	26.34 ± 4.37	>.05
Smoking history
Yes	58 (42.03%)	95 (46.12%)	.673
No	80 (57.97%)	111 (53.88%)
Blood lipid profile
TC (mmol/L)	3.95 ± 0.72	4.01 ± 0.85	.321
TG (mmol/L)	2.11 ± 0.68	1.93 ± 0.37	.132
HDL (mmol/L)	1.11 ± 0.09	1.02 ± 0.17	.319
LDL-C (mmol/L)	2.55 ± 0.34	2.47 ± 0.72	.365

Abbreviations: BMI = body mass index, CAG = coronary arteriography, FFR = fractional flow reserve, HDL = high-density lipoprotein, LDL-C = low-density lipoprotein cholesterol, TC = total cholesterol, TG = triglyceride.

3.2. Comparison of treatment methods

We compared the treatment methods of the 2 groups. As shown in Table 2, 122 (88.41%) patients in the CAG group and 90 (43.69%) patients in the CAG + FFR group received surgical treatment, with significant differences (P = .017). The CAG + FFR group showed a 44.72% reduction in the need for surgical treatment, effectively preventing overtreatment. There was no significant difference in the average number of lesions per 10 patients between the 2 groups (P = .870). Furthermore, the CAG group had a statistically higher average number of stents per patient (0.7320 ± 0.046) compared to the CAG + FFR group (0.5612 ± 0.073) (P = .021).

Table 2.

Comparison of treatment methods between the 2 groups.

	CAG group (n = 138)	CAG + FFR group (n = 206)	P value
Surgical treatment	122 (88.41%)	90 (43.69%)	.017
PCI	116 (84.06%)	84 (40.78%)
OPCAB	6 (4.35%)	6 (2.91%)
No surgical treatment	16 (11.59%)	116 (56.31%)
Average number of lesions per 10 patients	1.278 ± 0.324	1.037 ± 0.278	.870
Average number of stents per patient	0.7320 ± 0.046	0.5612 ± 0.0730	.021

Abbreviations: CAG = coronary arteriography, FFR = fractional flow reserve, OPCAB = off-pump coronary artery bypass, PCI = percutaneous coronary intervention.

3.3. MACE at 6-month follow-up after surgery

After treatment, we recorded the occurrence of MACE during a 6-month telephone follow-up, which included angina pectoris, myocardial infarction, and sudden cardiac death. In the CAG group, there were 9 cases (6.52%) of angina pectoris and 3 cases (2.17%) of myocardial infarction, while in the CAG + FFG group, there were 16 cases (7.77%) of angina pectoris and 5 cases (2.43%) of myocardial infarction (Table 3). No sudden cardiac deaths were observed in either group. At 6 months after surgery, all MACE showed no significant differences between the 2 groups (P > .05).

Table 3.

Comparison of MACE between the 2 groups.

	CAG group (n = 138)	CAG + FFR group (n = 206)	χ2	P value
Angina pectoris	9 (6.52%)	16 (7.77%)	1.34	.74
Myocardial infarction	3 (2.17%)	5 (2.43%)	0.66	.59
Sudden cardiac death	0 (0.00%)	0 (0.00%)	0.00	.89

Abbreviations: CAG = coronary arteriography, FFR = fractional flow reserve, MACE = major adverse cardiovascular events.

3.4. Presentation of typical cases

Case 1 was a 50-year-old male presenting with CHD, intermittent chest tightness, and shortness of breath. Upon admission, the electrocardiogram indicated atrial fibrillation (Fig. 1A). Subsequent CAG and FFR examination revealed a 75% stenosis in the anterior descending artery (Fig. 1B). While the anatomical stenosis suggested a need for stent implantation or coronary artery bypass graft, the FFR test indicated a value of 0.87 (Fig. 1C), which did not detect functional ischemia. As a result, no intervention was performed to avoid excessive treatment. Instead, the patient received standardized drug treatment for CHD, leading to a significant improvement in chest tightness and shortness of breath during follow-up.

Figure 1.

A 50-year-old male with CHD presenting symptoms of intermittent chest tightness and shortness of breath. (A) Abnormal electrocardiogram findings of atrial fibrillation. (B) CAG showed that LAD stenosis was 75% (arrow). (C) FFR value was 0.87.

Case 2 was a 62-year-old male with CHD presenting intermittent chest tightness and shortness of breath. The admission electrocardiogram showed sinus bradycardia (Fig. 2A). CAG and FFR examinations revealed an 85% stenosis in the left anterior descending branch (LAD) (Fig. 2B) with an FFR of 0.72 (Fig. 2C), as well as 75% stenosis in the circumflex branch, 85% stenosis in the first diagonal branch, and 75% stenosis in the middle branch (Fig. 2D). The right coronary artery (RCA) exhibited a 75% stenosis (Fig. 2E). The FFR evaluation indicated a negative result. The CAG findings suggested the need for 5 stents due to anatomical stenosis, but FFR indicated that only 1 stent was deemed necessary to avoid overtreatment. Subsequently, a 3.0*29 mm stent was implanted in the LAD, resulting in an FFR of 0.95. Following the procedure, the patient received standardized drug treatment for CHD, leading to a significant improvement in the patient’s symptoms.

Figure 2.

A 62-year-old male with CHD presenting symptoms of intermittent chest tightness and shortness of breath. (A) The electrocardiogram showed abnormal ST-T changes in sinus rhythm. (B) The LAD artery demonstrated 85% stenosis at its proximal section (arrow). (C) The FFR test yielded a value of 0.72. (D) There was 75% stenosis of the circumflex branch, 85% stenosis of the first diagonal branch, and 75% stenosis of the intermediate branch (arrow). (E) There was 75% stenosis in the RCA (arrow).

Case 3 was an 84-year-old woman with CHD who presented with intermittent chest tightness and shortness of breath. The electrocardiogram upon admission revealed extensive ST-T changes (Fig. 3A). Myocardial zymogram results were negative. CAG and FFR examinations indicated 80% stenosis in the LAD artery segment 7 (Fig. 3B) with FFR of 0.83 (Fig. 3C), 80% stenosis in the circumflex artery (Fig. 3D) with FFR of 0.81 (Fig. 3E), and 75% and 90% stenosis in the second and third segments of the RCA, respectively (Fig. 3F). The FFR test result was 0.88 (Fig. 3G). Based on the previously identified anatomical stenoses, it was determined that the patient required 4 stents: 1 for the LAD artery, 1 for the circumflex artery, and 2 for the RCA. The FFR examination revealed no functional ischemia in the distal parts of all stenoses, negating the need for stent placement and averting excessive stent implantation. After treatment, the patient’s symptoms of chest tightness and shortness of breath improved significantly.

Figure 3.

A case of an 84-year-old woman with CHD experiencing intermittent chest tightness and shortness of breath. (A) The electrocardiogram showed abnormal ST-T changes in sinus rhythm. (B) There was 80% stenosis in the LAD (arrow). (C) FFR test indicated a value of 0.83 for the LAD stenosis. (D) There was 80% stenosis in the circumflex artery (arrow). (E) FFR test indicated a value of 0.81 for the 80% stenosis of the circumflex artery. (F) There was 75% stenosis in the second segment of the RCA, and 90% stenosis in the third segment (arrow) (F), with an FFR test result of 0.88 (G).

4. Discussion

CHD refers to the narrowing or blockage of the coronary arteries caused by atherosclerosis, resulting in impaired blood and oxygen supply to cardiomyocytes, ultimately leading to their apoptosis and necrosis.^[9,10] Apart from the widely used CAG, which is considered the gold standard in clinical practice for diagnosing CHD, other common methods to assess the extent of vascular disease or determine the nature of plaques include intravascular ultrasound and optical coherence tomography.^[11,12] Since a single myocardium can receive blood supply from multiple vessels simultaneously, identifying the culprit vessel becomes challenging. Therefore, FFR has emerged as a novel tool capable of directly assessing myocardial functional ischemia, thereby challenging the longstanding indispensable role of CAG in the diagnosis and treatment of CHD.^[13]

CAG alone can only provide an anatomical assessment of stenosis severity, rather than a measurement of myocardial ischemia.^[7] As a result, the degree of stenosis may be overestimated, leading to potential overtreatment. A previous study demonstrated that nearly a quarter of patients with coronary artery stenosis exceeding 70% did not exhibit myocardial ischemia, indicating that intervention based solely on CAG results may be ineffective and could increase both the economic and psychological burden on patients.^[14] In our study, we enrolled patients with coronary artery stenosis exceeding 70%, encompassing a variety of lesion morphologies such as multivessel disease, single-vessel lesion, diffuse stenosis, and bifurcation lesion. Furthermore, there were no statistically significant differences between the CAG and CAG + FFR groups in terms of age, gender, underlying disease, BMI, smoking history, and blood lipid profile. However, patients who were examined by FFR had a significantly lower rate of unnecessary surgical treatments. Additionally, we observed a substantial reduction in the number of stents used in the CAG + FFR group compared to the CAG group. At the 6-month follow-up after surgery, all MACE, including angina pectoris, myocardial infarction, and sudden cardiac death, exhibited no significant differences between the 2 groups. However, it might be necessary to conduct a prospective study with a long-term follow-up for further investigation.

While this study provides valuable insights into the utilization of FFR in patients with significant coronary artery stenosis, we recognize that applying FFR measurements to all patients without stratifying by initial severity classifications may introduce a selection bias. The guideline-recommended use of FFR primarily applies to patients with moderate stenosis. By applying it universally in our cohort, we may have created confounding variables that affect the outcomes presented. Future studies should be more targeted in their application of FFR based on clinical guidelines.

This study is not without limitations. A significant limitation is the universal application of FFR measurements to all patients with >70% stenosis. While the rationale was to investigate the functional significance of coronary lesions comprehensively, this approach may have introduced selection bias as FFR measurements are generally recommended for moderate stenosis. The results may not fully align with the established clinical guidelines in this regard, and further research that adheres strictly to guideline recommendations is necessary for a more accurate assessment of FFR’s clinical utility. Moreover, this study is limited by being single-centered with a relatively short follow-up time. Therefore, further multi-center prospective studies are needed. Additionally, it has been reported that the high cost of FFR equipment and consumables, as well as issues such as heart rhythm disturbances, myocardial microcirculation congestion caused by pressure wires and vasodilators, and X-ray radiation, need to be urgently addressed.^[15,16] Considering the rapid advancements in artificial intelligence and big data, virtual FFR technology, based on anatomical information of coronary arteries, can calculate and generate virtual FFR values without the use of pressure wires and vasodilators during the examination process.^[17] With improved safety and universality, virtual FFR technology may represent the frontier for guiding the diagnosis and treatment of CHD in the future.

In conclusion, our findings demonstrated that after combining CAG with FFR, there was a notable 44.72% decrease in the number of CHD patients with coronary artery stenosis exceeding 70% needing surgical intervention. This study has concluded that FFR-guided surgical treatment for CHD can effectively prevent overtreatment and improve treatment accuracy.

Author contributions

Conceptualization: Sheng Li.

Data curation: Liying Zhang, Dingxiong Xie, Bo Zhang, Yunlong Zhang, Bing Li, Zheng Zhang.

Formal analysis: Liying Zhang, Dingxiong Xie, Yanzhen Wang, Jianjian Jin.

Funding acquisition: Liying Zhang, Yirong Gan.

Investigation: Liying Zhang, Dingxiong Xie, Yirong Gan, Jing Xie, Bo Zhang, Yunlong Zhang, Bing Li, Rui Mao.

Methodology: Zongke Kou, Xiaoqing Kou, Rui Mao, Tianxiang Liang.

Project administration: Sheng Li, Zheng Zhang.

Software: Liying Zhang, Dingxiong Xie, Jianjian Jin.

Supervision: Dingxiong Xie, Yanzhen Wang.

Writing – original draft: Liying Zhang, Dingxiong Xie.

Writing – review & editing: Yirong Gan, Yanzhen Wang, Jing Xie, Bo Zhang, Zongke Kou, Yunlong Zhang, Bing Li, Xiaoqing Kou, Rui Mao, Jianjian Jin, Tianxiang Liang, Sheng Li, Zheng Zhang.