Access to side branches with a sharply angulated origin: usefulness of a specific wire for chronic occlusions

INTRODUCTION

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome (SCA). However, especially in women, it has been identified as the underlying pathophysiological mechanism in a growing percentage of cases. SCAD is defined as the separation of the coronary artery wall layers not associated with trauma, iatrogenesis, atherosclerosis or extension of an aortic dissection.1 Clinical signs are myocardial ischemia and are due to the coronary flow limitation that alters the arterial parietal structures.

The first description ever reported by Pretty2 back in 1931 was followed by the description of isolated cases and small series for years. However, we have recently seen a significant increase of information on SCADs lately. Nowadays, clinical profile, diagnostic and therapeutic approach, and prognosis can be found in the SCAD and they vary significantly compared to atherosclerosis—the most common cause of ACS.3,4 Even the European Society of Cardiology5 and the American Heart Association6 have recently published 2 consensus documents on this disease.

In light of the growing evidence and in an attempt to enrich it, back in 2010 our center started a specific program of diagnosis and follow-up of patients with SCAD. The results and conclusions are presented here.

METHODS

All cases of SCAD were collected prospectively since 2010. Diagnosis, treatment, and follow-up were centralized and unified according to the scientific evidence available at the time. Given the length of the study period (9 years) and the extensive medical literature available on this issue over the years, new aspects in the assessment of patients (such as fibromuscular dysplasia [FMD]) have been introduced gradually. This protocol and the data collection book were approved by our center ethics committee and registered in a validated repository (NCT03607981). The patients’ informed consents were obtained in all cases.

Clinical information and follow-up

The demographic characteristics, the patients’ personal past medical histories, data at admission, and disease progression were collected in the clinical history at admission and follow-up in a SCAD monographic review (T. Bastante). The coronary angiography and intravascular imaging studies were analyzed by 3 expert interventional cardiologists (T. Bastante, M. García-Guimaraes, and F. Alfonso) and the final diagnosis of SCAD was only established if they all agreed unanimously. The use of intracoronary imaging modalities (intravascular ultrasound [IVUS] or optical coherence tomography [OCT]) was left to the operator’s discretion. However, it was recommended in cases of suspicious diagnosis (especially type 2 and 3 SCADs according to Saw angiographic classification7) or need to perform PCI as long as the segment under study was accessible and in a not overly tortuous artery. When the OCT was used, the intracoronary image was classified as double lumen when the separation of the arterial layers originated true and false lumens, both with lack of refraction due to complete contrast washout. Intramural hematoma was defined as the separation of arterial layers occupied by moderately refracting material with an attenuation consistent with intraparietal bleeding without complete contrast washout. Both the IVUS and the OCT tried to identify the communication between the false and the true lumen and the presence of thrombotic material in the latter (figure 1 shows typical examples). The initial recommended treatment was a wait-and-see conservative approach and the PCI was only performed in cases of clinical instability or symptom persistence. During admission, and as long as it was possible, a coronary computed tomography (CT) scan was performed for a better characterization of coronary lesions. This information was used during follow-up as a comparative pattern in a new coronary CT scan to confirm the healing of the SCAD or in the reappearance of symptoms for reevaluation purposes. Patients with a diagnosis suggestive, but not definitive, of SCAD were scheduled to receive a control coronary angiography within the following months.

Figure 1. Images of angiography (A-C) and optical coherence tomography (OCT) (D-I). A: type 1 spontaneous coronary dissection (SCAD) in the medial portion of the left anterior descending coronary artery. The arrows point to the characteristic imaging of double lumen with linear intraluminal filling defect outlined by contrast (video 1 of the supplementary data). B: type 2 SCAD in distal left anterior descending coronary artery and diagonal branch. The arrows point to the sudden loss of vessel caliber with length > 20 mm (video 2 of the supplementary data). C: type 3 SCAD in obtuse marginal artery. The arrows point to focal stenosis with length < 20 mm similar to an atherosclerotic lesion (video 3 of the supplementary data). D-F: OCT images showing the double lumen morphology (TL, true lumen; FL, false lumen). Note the unusual image of subintimal calcium displaced with the flap (++). G-H: morphology of intramural hematoma (IMH). I: entry (arrow) with partially thrombosed false lumen. The asterisk (*) shows guidewire artifact.

Definitions

In order to classify the angiographic patterns of SCAD, the aforementioned specific classification developed by Saw et al.7 was used (figure 1 shows examples of this). Two different criteria of success were established for cases where a PCI was required. In the first place, conventional procedural success was defined as a final TIMI flow grade 2-3 (Thrombolysis in Myocardial Infarction) with residual stenosis < 30% after stent/scaffold implantation or < 50% after simple balloon angioplasty. Secondly, the PCI-SCAD was considered successful with flow improvements ≥ 1 grade in the TIMI score and a final TIMI flow grade of 2-3.8 Major cardiovascular adverse events (MACE) at the follow-up included all-cause mortality, reinfarction, unscheduled revascularization, ventricular arrhythmia, heart failure, and stroke.

Screening of extracoronary vascular abnormalities

Since 2013 and as long as it was possible, a selective angiography of both renal and iliac arteries during the diagnostic coronary angiography was performed. Also, 3 to 6 months after the event, the study was completed using the angio-CT scan to examine the floor of the middle cranial fossa up to the femoral arteries (modification of the protocol published by Liang et al.9) including intracranial vessels, supra-aortic trunks, the aorta, and mesenteric, renal, and iliac branches. FMD was defined as the presence of focal narrowing separated by dilatation areas with the traditional «pearl necklace» appearance (multifocal shape) or the presence of tubular focal lesions (unifocal shape). Aneurysms were defined as dilatations > 50% with respect to the caliber of the normal, adjacent arterial segment. Dissection was defined as a double lumen morphology in the arterial segment. The screening of extracoronary vascular abnormalities (EVA) was considered complete when the intracranial territories, supra-aortic trunks, the aorta, and the splanchnic, renal, and iliac territories all had been examined (using angiography, angio-CT scan or both).

Statistical analysis

Quantitative variables were expressed as mean ± standard deviation or median [interquartile range] according to their distribution. Categorical variables were expressed as numbers (percentage). The analysis was conducted using the STATA 12 statistical software package (StataCorp LLC, United States).

RESULTS

Between January 2010 and December 2018 our center performed 12 951 diagnostic coronary angiographies that identified 37 SCADs (41 lesions) in 33 patients (0.28%). Prevalence among the coronary angiographies performed due to ACS (4185) was 1%, although prevalence among women in this context rose to 3%. If the percentage of patients with a final diagnosis of SCAD in the group of women with ACS under 50 is analyzed, prevalence rose to 12.5%. There are more diagnoses over the years from 1 or 2 patients per year initially to 5-7 annual patients over the last period (figure 1 of the supplementary data).

The baseline characteristics of the patients included in the study are shown on table 1. Most (97%) were middle-aged women (56 ± 12 years). Only 7 women (21%) had no traditional cardiovascular risk factors. Five patients (15%) had a personal past medical history of ischemic heart disease, 2 of them with a confirmed diagnosis of SCAD. A study conducted a posteriori confirmed that the remaining 3 patients showed clinical signs consistent with an initially misdiagnosed SCAD (ACS with coronary arteries interpreted as normal, 1 of them in the peripartum).

Table 1. Baseline characteristics of the patients

	n = 33
Women	32 (97)
Age (years)	56 ± 12
Race
Caucasian	28 (85)
Other	5 (15)
Cardiovascular risk factors
Smoking habit
Current smoker	9 (27)
Former smoker	7 (21)
Hypertension	12 (36)
Hypercholesterolemia	14 (42)
Diabetes	2 (6)
Family history of ischemic heart disease	4 (12)
Family history of SCAD	2 (6)
Relevant findings
Previous diagnosis of ischemic heart disease	5 (15)
Confirmed diagnosis of previous SCAD	2 (6)
Chronic inflammatory disease	3 (9)
Depressive disorder	5 (15)
Anxiety disorder	9 (27)
History of hypothyroidism	11 (33)
Gynecological/obstetric past medical history	n = 32
Menopause	24 (75)
Menopause age (years)	49 ± 4
Hormone replacement therapy	2 (7)
Oral hormonal contraceptive	1 (3)
Intrauterine device	1 (3)
Nulliparous	3 (9)
Multiparous	18 (44)
History of miscarriage	3 (9)
SCAD, spontaneous coronary artery dissection. Data are expressed as no. (%) or mean ± standard deviation.

Table 2 shows the characteristics at hospital admission and during the angiographic assessment. All patients presented with myocardial infarction, most of them (73%) with non-ST-elevation acute myocardial infarction. There was a trigger factor in one third of the cases; the most common was emotional stress (21%) followed by intense physical exercise (9%). Presentation at the peripartum was rare (1 patient only). The artery most frequently compromised was the left anterior descending coronary artery (51%). Eighteen percent of the patients had multivessel disease. Intracoronary imaging modalities (IVUS or OCT) were used in 42% of the cases, mostly OCT (33%). Sixteen lesions in 14 patients were assessed. Those assessed through the OCT confirmed the presence of fenestration between the false and the true lumen in 7 lesions (58%). There were no images consistent with thrombi in the true lumen in any of the cases assessed using intracoronary imaging modalities.

Table 2. Characteristics of the patients at hospital admission and in the angiographic assessment

	n = 33
Clinical diagnosis at admission
STEMI	9 (27)
NSTEMI	24 (73)
Event-triggering factors	11 (33)
Intense physical exercise	3 (9)
Emotional stress	7 (21)
Peripartum	1 (3)
Angiographic characteristics	n = 33 (41 lesions)
Access
Radial	29 (88)
Femoral	4 (12)
Diseased vessel
Left anterior descending coronary artery	21 (51)
Circumflex artery	10 (24)
Right coronary artery	10 (24)
Diseased segment
Proximal	10 (24)
Medial	11 (27)
Distal	20 (49)
Secondary branches	18 (44)
Multivessel disease	6 (18)
Multi-segment disease	13 (32)
Saw et al. angiographic classification7
Type 1	6 (15)
Type 2	32 (78)
Type 3	3 (7)
Percentage of stenosis (visual estimate)	77 ± 24
Length of the lesion (mm)	41 ± 28
Initial TIMI flow grade
0	5 (12)
1	5 (12)
2	1 (2)
3	3 (73)
Intracoronary imaging modality	n = 14 (16 lesions)
IVUS	4 lesiones
Fenestration	0
Thrombus	0
OCT	12 lesions
Double lumen	7 (58)
Intramural hematoma	2 (16)
Both	3 (25)
Fenestration	7 (58)
Thrombus	0
CT, computed tomography; IVUS, intravascular ultrasound; NSTEMI, non-ST-elevation acute myocardial infarction; OCT, optical coherence tomography; STEMI, ST-segment elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction. Data are expressed as no. (%) or mean ± standard deviation.

Table 3 shows treatment and the in-hospital disease progression. Initial conservative treatment was the first option in most cases (82%). Only 6 patients were treated with PCI as the initial strategy, 4 of them due to progressive flow worsening with the injections of contrast. The PCI conventional success was reported in 50% of the cases, and the PCI-SCAD success in 67% of the cases. One iatrogenic dissection was reported in the left main coronary artery.

Table 3. Management and in-hospital disease progression of patients

	n = 33
Initial treatment
Conservative	27 (82)
PCI	6 (18)
PTCA-balloon	2 (6)
Bare-metal stent	2 (6)
Drug-eluting stent	1 (3)
Bioresorbable vascular scaffold device	1 (3)
Results from the PCI group	n = 6
Conventional success	3 (50)
PCI-SCAD success	4 (67)
In-hospital disease progression	n = 33
Peak troponin T levels (ng/mL)	378 [132-1705]
Peak creatine kinase levels (U/L)	403 [169-1181]
Left ventricular dysfunction [LVEF < 50%]	5 (17)
Segmental abnormalities on the TTE	17 (52)
MACE	5 (15)
Death	0
Reinfarction	0
New coronary angiography	4 (12)
Unplanned revascularization	3 (9)
PCI group (n = 6)	2 (33)
Conservative management group (n = 27)	1 (4)
Ventricular tachycardia/fibrillation	2 (6)
Heart failure	1 (3)
Hospital stay (days)	4 [3-7]
Coronary CT scan at admission	n = 19 (58)
SCAD visible on the coronary CT scan	15 (79)
Treatment at hospital discharge	n = 33
ASA	31 (94)
Clopidogrel	9 (27)
Ticagrelor	5 (15)
Prasugrel	0
Dual antiplatelet therapy	14 (42)
Anticoagulation	2 (6)
Beta-blockers	28 (85)
ACEI/ARA II	21 (64)
Statins	25 (76)
Nitrates	3 (9)
Calcium antagonists	3 (9)
ACEI, angiotensin-converting enzyme inhibitors; ARA-II, angiontensin II receptor antagonist; ASA, acetylsalicylic acid; CT, coronary tomography; LVEF, left ventricular ejection fraction; MACE, major cardiovascular adverse events; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; SCAD, spontaneous coronary artery dissection; TTE, transthoracic echocardiography. Data are expressed as no. (%) or mean ± standard deviation or median [interquartile range].

During in-hospital disease progression no patient died or suffered any reinfarctions. However, a new coronary angiography was required in 4 patients with symptoms. Except for the patient with a left main coronary artery iatrogenic dissection initially treated with conservative treatment no case was due to failed initial conservative treatment. The remaining 3 patients had acute stent thrombosis, SCAD of a vessel other than the index, and progression of the SCAD adjacent to the segment treated with the stent. Overall, the rate of in-hospital MACE was 15% and events focused on patients who required PCI. Acetylsalicylic acid (ASA) was prescribed to 94% of the patients at hospital discharge and dual antiplatelet therapy to 14 patients only (42%) of whom 7 required PCI. Fifty-eight percent of the patients received coronary CT scans during admission and images consistent with SCAD were found in 79% of the cases.

Table 4 shows out-of-hospital disease progression. Median follow-up was 33 months [13-49], the overall rate of events was 18%. Two deaths were reported, 1 due to cardiovascular causes (sudden death 6 years after the SCAD) and the other due to non-cardiovascular causes (sepsis in the abdominal postoperative). Only 1 patient required a new revascularization due to restenosis of the stent implanted to treat the SCAD. Three out of the 4 patients (12%) with SCAD relapse had suffered events prior to the index event that were compatible with SCAD; that is, each one of them had presented with, at least, 3 events. Except for 1 recurrence at the 7-month follow-up, most events occurred more than 2 years after the index event (figure 2). Regarding pharmacological treatment, ASA was kept for a median 17 months [9-35] after the event and the second antiplatelet drug was withdrawn early in most of the patients. Of the patients who received conservative treatment, only 25% were still on dual antiplatelet therapy 6 months after the event (median 0 months [0-6]). In those patients who required PCI, dual antiplatelet therapy was keep for a median 5 months [1-7].

Table 4. Out-of-hospital disease progression and follow-up of the patients

	n = 33
Follow-up time (months)	33 [13-49]
MACE	6 (18)
Death	2 (6)
New AMI	3 (9)
Recurrence	4 (12)
New revascularization	1 (3)
Heart failure	1 (3)
Stroke	1 (3)
Time on ASA (months)	17 [9-35]
Time on dual antiplatelet therapy (months)
Conservative treatment group	0 [0-6]
PCI group	5 [1-7]
Control SCAD	n = 16 (48)
Coronary CT scan	9
Planned	6
Due to symptoms	3
Invasive coronary angiography	11
Planned	3
Due to symptoms	8
Screening of EVA	N = 32 (97)
Type of screening
CT scan	18 (56)
Angiography	5 (16)
Angiography + CT scan	9 (28)
Complete screening	28 (88)
EVA data	19 (59)
Type of EVA
Fibromuscular dysplasia	15 (47)
Aneurysm	5 (15)
Other	1 (3)
Location of EVA
Renal arteries	9 (28)
Iliac arteries	7 (22)
Supra-aortic trunks	5 (16)
Intracranial	3 (9)
Other	5 (16)
AMI, acute myocardial infarction; ASA, acetylsalicylic acid; CT, computed tomography; EVA, extracoronary vascular abnormalities; MACE, major cardiovascular adverse events; PCI, percutaneous coronary intervention; SCAD, spontaneous coronary artery dissection. Data are expressed as no. (%) or mean ± standard deviation or median [interquartile range].

Angiography control was performed in 48% of the patients, in 9 of them using coronary CT scan and invasive coronary angiography in 11 patients. The coronary CT scan was performed in 3 patients in the context of a new episode of chest pain. After comparing it with the previous CT scan performed at the index event, the new SCAD was discarded (figure 3). However, most coronary angiographies were performed in the context of a new cardiac event; only 3 patients received a planned control coronary angiography. Out of the 16 patients on angiographic control, imaging improved with restitutio ad integrum in 75% of them. Six months after the SCAD, the documented rate of resolution rose to 86%.

Figure 2. Fifty-five-year old woman with non-ST-elevation acute myocardial infarction (NSTEMI). She had experienced 2 previous acute myocardial infarctions with «normal coronary arteries» according to the coronary angiography. A: sudden caliber loss with tapering until the occlusion in the medial-distal portion of the left anterior descending coronary artery compatible with spontaneous coronary artery dissection (SCAD); conservative treatment. B: tortuous obtuse marginal artery without evident abnormalities. Two years later new hospitalization due to NSTEMI. C: caliber and flow recovery in the anterior descending coronary artery. D: obtuse marginal artery with sudden caliber loss and tapering (compare to B) compatible with SCAD; conservative treatment. E-F: selective angiographies of left renal and left iliac arteries with fibromuscular dysplasia.

Figure 3. Fifty-three-year old woman with non-ST-elevation acute myocardial infarction. After a tortuous segment, the sudden caliber loss of the left anterior descending coronary artery with vessel tapering can be seen (arrows) on the coronary angiography (A) and coronary computed tomography (CT) scan (B) compatible with a spontaneous coronary artery dissection (SCAD) at the medial-distal portion of the left anterior descending coronary artery. Four years later, the patient presents to the ER with prolonged chest pain without alterations on the ECG or high markers of myocardial damage. The coronary CT scan shows the coronary arteries without images indicative of SCAD. C: left anterior descending coronary artery. D: right coronary artery. E: circumflex artery.

Figure 4. Forty-five-year old woman with non-ST-elevation acute myocardial infarction. The coronary angiography (A) shows a spontaneous coronary artery dissection at the medial-distal portion of the left anterior descending coronary artery (arrows). During catheterization the selective coronary angiography performed on the right renal (B) and left iliac arteries (C) shows wall irregularities compatibles with fibromuscular dysplasia (arrows). D: coronary computed tomography angiography at the follow-up with findings compatible with fibromuscular dysplasia on the left external iliac artery (arrows); note the greater sensitivity of coronary angiography (C) for the detection of subtle parietal abnormalities compared to coronary computed tomography angiography (D).

The screening of EVA was performed in 97% of the patients (full screening in 88%). Fifty-nine percent of the patients showed abnormalities that went up to 61% when the screening of EVA was complete. The abnormality most commonly found was FMD (47%) followed by arterial aneurysms (in 5 patients, 3 of which were intracranial aneurysms). The renal and iliac arteries were the most commonly compromised arteries of all: half of the patients studied showed abnormalities in either one of these arteries (examples in figure 2 and figure 4). After the study, the stroke team indicated the closure of the 3 intracranial aneurysms.

DISCUSSION

This study prospectively reports on the results of a current series of patients with SCAD with an updated and systematized diagnostic-therapeutic process and prolonged clinical follow-up. The clinical profile is consistent with what it is known about this disease:3,8,10 middle-aged woman with risk factors and low concomitance of chronic inflammatory disorders, autoimmune diseases or collagen diseases. Both the presentation and the angiographic characteristics were consistent with what has already been described: non-ST-elevation acute myocardial infarction that damaged the medial-distal segments and secondary branches predominantly with a higher incidence reported on the left anterior descending coronary artery. The most common Saw angiographic classification was type 2. Comparatively, in this series, the use of intracoronary imaging modalities was superior to other larger and recent series (42% vs 7.6% and 13% in the series of Saw et al.10 and Tweet et al.,8 respectively); this brings high reliability in the inequivocal diagnosis of SCAD. The most important conclusions of intracoronary imaging are: a) when OCT was the imaging modality used, the fenestration of both lumens could be identified in half of the lesions; b) the presence of mixed patterns (double lumen and intramural hematoma) within the same lesion is not an uncommon finding, which supports the evolutionary theory between both patterns; and c) lastly and probably the most important conclusion of all, intraluminal thrombi were not found in any of the lesions studied.

As it has already been described, an initial wait-and-see conservative approach with no interventions seems to bring good results to patients with SCAD.8,10,11 The rate of in-hospital MACE was low (15%). No deaths were reported, and bailout revascularizations were not necessary in any of the patients who received conservative treatment, except for 1 case due to iatrogenic dissection of left main coronary artery during the initial catheterization. Also, during the patients’ initial disease progression, they already showed preserved left ventricular ejection fraction. Similarly, out-of-hospital disease progression was good: 2 deaths were reported (1 due to non-cardiovascular causes) at the 2.7-year median follow-up, and 12% had a new episode of SCAD. These are similar data to those described in a Canadian series12 (10.4% at the 3.1-year median follow-up) and significantly lower to the rate of recurrence of 27% at the 2.3-years of median follow-up reported by Mayo Clinic.8

Unlike the atherosclerosis related ACS, in SCAD the ideal antithrombotic therapy has not been totally established. It seems logical to avoid aggressiveness, especially when 1 of the most plausible etiopathogenic theories is intraparietal bleeding of vasa vasorum as the initial event.13,14 Therefore, given the lack of intraluminal thrombus in a high percentage of patients studied with IVUS and OCT in this series a low-intensity antithrombotic therapy was used. ASA was kept for an average 1.5 years and the second antiplatelet drug was only indicated at hospital discharge in patients who required PCI and for the shortest period of time possible. The satisfactory disease progression reported with rates of out-of-hospital events consistent with those reported in other large series (from 10% to 20%)1 and the low rate of recurrence suggest that low-intensity antithrombotic therapy can be an excellent option for these patients.

There is very little information on the value of coronary CT scan during SCAD related hospitalizations. It was performed in 58% of patients from this series and SCAD was identified in three fourths of the cases. A more extensive analysis of these findings has been recently published by our group.15 The current study shows that this information was very useful in the follow-up of 3 patients to discard new episodes of SCAD and avoid the coronary angiography and associated risks for the patients (3.4% of iatrogenic dissections in patients with SCAD).16 However, in one fourth of the patients the SCAD could not be identified in the acute phase not even with the previous coronary angiography as guidance. Therefore, the value of coronary CT scan as an early diagnostic imaging modality is limited in this context.

Back in 2012 the association between SCAD and FMD17 was described for the first time, and later studies only not confirmed the high prevalence of this association but also of other EVA (aneurysms, dissections, and thrombosis).18-20 In the European consensus document recently published the screening of EVA is recommended in patients with SCAD.5 To our knowledge and up to this day this study shows the results of the most complete screening of FMD and other EVA. With a study in 97% of the patients—complete in 88%—the great presence of EVA (60%) confirms this interesting association. The need to conduct these studies may be put into question since most findings are associated with discrete and typical parietal abnormalities of FMD that do not lead necessarily to significant functional disorders. As a matter of fact, after the long follow-up of patients and despite the high prevalence of EVA, the extracardiac arterial events reported were only 1 stroke. However, there are 3 reasons to support the screening: a) in case of suspicious diagnosis, it may be the key to confirm the diagnosis of SCAD;21 b) knowing arterial parietal structural alterations can be useful for the diagnosis and treatment of future extracardiac events; and c) the finding of intracranial aneurysms is not negligible (9% in our series, but up to 14% in the Canadian series16) and it is relevant due to the risk of intracranial bleeding and secondary morbimortality. As a matter of fact, in 3 of our patients a percutaneous coronary intervention was indicated to seal the intracranial aneurysm.

Limitations

The main limitations of this study are the small size of the sample and the fact that it focused on a single center only. However, this study has a long follow-up with a unified treatment given the centralization of the patients.

CONCLUSIONS

In our center the centralization and protocolization of patients with SCAD systematized both treatment and the performance of additional tests. Intracoronary imaging allows us to confirm diagnosis in angiographically suspicious cases without showing any thrombi in the true lumen whatsoever. A low-intensity antithrombotic strategy with ASA only and for a limited period of time seems to give good results in the management of SCADs with conservative treatment. The high rate of spontaneous resolution of SCAD was confirmed in the 6-month images. Over half of the patients with SCADs show some EVA. Performing a coronary CT scan in the acute phase was useful, comparatively speaking, in new events and scheduled controls.

CONFLICTS OF INTEREST

F. Alfonso is an associate editor of REC: Interventional Cardiology; the editorial protocol of the journal was observed to guarantee an impartial manuscript handling.

 

REFERENCES

INTRODUCTION

Percutaneous coronary interventions (PCI) of chronic total coronary occlusions (CTO) represent up to 12% of all PCIs performed.1 The reason to perform the percutaneous recanalization of a CTO is to improve clinical symptoms which, ultimately, has potential survival benefits as suggested by some observational studies.2^-4 However, the clinical benefits of successful recanalization remain undefined and to this day accepting that opening CTOs saves lives, despite the favorable consistent results from several contemporary registries, is still not supported by randomized clinical trials.5

Given the complexity of these procedures, a specific program with dedicated CTO-trained operators is encouraged. Also, most of the published registries and randomized clinical trials are performed in highly skilled centers and feature results in limited periods of time usually on specific devices, but not long-term results.2^-5

We present the results of a specific PCI program for CTO lesions, starting with the introduction of drug-eluting stents from 2002 through 2017. The profile of patients and lesions, procedural data, results, and long-term clinical outcomes have been analyzed during the time frame of the program.

METHODS

This prospective registry conducted in a single center with an active PCI program for CTOs started back in 2002. It included 1 single operator who would progressively develop proper skills.

All consecutive patients treated of their CTOs, at least once, through percutaneous recanalization during the period 2002–2017 were included. Clinical data, angiographic characteristics, and procedural features were collected. The patients gave their informed consent and the study was approved by the local review board.

The indication for the recanalization of the CTO was the presence of angina, confirmation of ischemia through provocation tests or viable myocardium assessed through magnetic resonance imaging since 2004 when this diagnostic imaging modality became available at our center. No angiographic exclusion criteria were applied. Therefore, long occlusions, severely calcified lesions, and ostial locations were included if clinically indicated. Patients with an indication for coronary artery bypass graft (CABG) were excluded.

CTOs diagnosed in the setting of an ST-segment elevation acute coronary syndrome were scheduled for intervention that was performed at least 4 weeks after the index procedure. In cases of non-ST-segment elevation, CTOs were approached during the initial catheterization or in a subsequent staged procedure at the operator’s discretion. Also, in 28 out of the 101 cases of CTOs diagnosed in the context of an ACS, the ad-hoc desobstruction of the CTO was attempted.

Most CTOs were performed by the lead operator who focused their experience on trying to improve the rate of success for the benefit of the patient.

For the analysis of temporal trends regarding techniques and results, patients were classified into 3 consecutive periods of time: 2002-2006, 2007-2011, and 2012-2017. Also, the entire cohort was divided into 2 groups regarding success or failure in the recanalization of the CTO. Follow-up data were obtained from hospital records and the contact kept with the patients and the information provided were prospectively included in a database. No routine angiographic follow-up assessment was conducted.

Procedures were performed according to standard practices through the femoral or radial approach. Antithrombotic therapy consisted of unfractionated heparin (100 U/Kg) with additional administration when appropriate, to achieve activated clotting times of 250 seconds or 300 seconds using the antegrade and retrograde approaches, respectively. Aspirin 100 mg was administered orally prior to the PCI. Before stent implantation patients received perioperatively 300 mg to 600 mg of clopidogrel followed by a daily administration of 75 mg for the prescribed period of dual antiplatelet therapy.

CTOs were defined as coronary obstructions with TIMI flow grade 0 of at least 3 months duration.

Procedural success was defined as achieving residual post-PCI stenosis < 30% associated with TIMI flow 2–3.

Mortality was considered cardiovascular unless an evident non-cardiac cause was identified. Myocardial infarction was defined according to the Third Universal Definition established by the European Society of Cardiology and the American College of Cardio- logy Foundation. Target lesion revascularization was defined as a repeated PCI on the target lesion or CABG on the target vessel following ischemia-driven restenosis. Target vessel revascularization was defined as repeated PCI or CABG on any segments of the target vessel. Major adverse cardiovascular events (MACE) were defined as cardiovascular death, myocardial infarction or need for surgical or percutaneous target vessel revascularization. Stent thrombosis was defined according to the Academic Research Consortium criteria.

The angiographic characteristics expected to be predictive of procedural success were classified according to the recommendations proposed by the Euro-CTO club consensus document.6 The J-score was calculated for each lesion based on the length of the occlusion, morphology of the stump, calcification, tortuosity, and prior attempt to open the CTO.7

Continuous variables were expressed as mean ± standard deviation or median (interquartile range [IQR]), when appropriate. Categorical variables were expressed as percentages. The chi square test or Fisher’s exact test were used to compare the categorical variables. The Kolmogorov-Smirnov test was used to verify the normal distribution of continuous data. Continuous variables were compared according to their distributions using the Student t test or Mann-Whitney U test (success vs failed subgroups), and the ANOVA or Kruskal-Wallis test (comparison of 3 time periods). The estimates of cardiovascular death-and-MACE-free survival were shown by the Kaplan-Meier curves. Inter-groupt differences were assessed using the log-rank test. The logistic regression and Cox proportional hazard models were used to assess the independent contribution of variables to procedural success and mortality, respectively. Multivariate models included variables with P values < .2 in the univariate analysis. All statistical analyses were 2-tailed, and P values < .05 were considered statistically significant. The statistical analysis was performed using the statistical software package SPSS 15.0 (SPSS Inc., United States).

RESULTS

A total of 424 CTOs (408 patients) were included. In 339 patients (80%) procedural success was achieved. The number of procedures and the corresponding rate of success per period is shown on figure 1 .

Figure 1. Number of procedures and corresponding rate of success per period.

The baseline characteristics regarding the success or failure of the CTO procedure are featured on table 1 and table 2. Previous CABG and the ACS setting were more common among failed cases. Patients with successful procedures were more prone to left anterior descending coronary artery (LAD) involvement, microchannels, and Rentrop grade 3 collateral blood flow. Procedural success was higher in the LAD compared to other target vessels (87% vs 77%; P = .02). Procedural success in the circumflex artery was the lowest of all (76%). The complexity of the CTO according to the J-score was higher in failed cases.

Table 1. Baseline characteristics

	All (n = 424)	Success (n = 339)	Failure (n = 85)	P
Age	63 ± 12	63 ± 12	64 ± 13	.48
Male sex	350 (83%)	277 (82%)	73 (86%)	.37
Hypertension	279 (66%)	217 (64%)	62 (73%)	.15
Diabetes Mellitus	120 (28%)	95 (28%)	25 (29%)	.91
Dyslipidemia	275 (65%)	222 (65%)	53 (62%)	.45
Past/current smoker	292 (69%)	236 (70%)	56 (66%)	.48
Previous infarction	147 (35%)	111 (33%)	36 (42%)	.72
Previous CABG	31 (7%)	18 (5%)	13 (15%)	.002
Multivessel disease	297 (70%)	234 (69%)	63 (74%)	.38
Left ventricular ejection fraction	55 ± 13	55 ± 13	57 ± 13	.17
Serum creatinine (mg/dL)	1.03 ± 0.53	1.02 ± 0.49	1.04 ± 0.64	.76
Acute coronary syndrome	103 (24%)	74 (22%)	29 (34%)	.021
CABG, coronary artery bypass graft. Data are expressed as no. (%) or mean ± standard deviation.

Table 2. Angiographic characteristics of occlusive lesions

	All (n = 424)	Success (n = 339)	Failure (n = 85)	P
Left anterior descending coronary artery	129 (30%)	112 (33%)	17 (20%)	.02
Right coronary artery	211 (50%)	163 (48%)	48 (56%)	.17
Left circumflex artery	81 (19%)	62 (18%)	19 (22%)	.39
Diameter (mm)	3.15 ± 0.45	3.15 ± 0.46	3.16 ± 0.58	.97
Length (mm)	23 ± 16	21 ± 13	29 ± 21	.001
Moderate-to-severe calcification	303 (74%)	232 (72%)	71 (84%)	.028
Moderate-to-severe tortuosity	150 (35%)	95 (28%)	55 (65%)	.001
Severe distal disease	122 (29%)	91 (27%)	31 (36%)	.14
Tandem occlusions	53 (13%)	31 (9%)	22 (26%)	.001
Microchannels	86 (20%)	75 (22%)	11 (13%)	.04
Ostial/side branch location	163 (38%)	120 (35%)	43 (51%)	.033
Tapered stump	208 (49%)	171 (50%)	37 (44%)	.12
Rentrop grade 3 collateral flow	206 (48%)	171 (50%)	35 (41%)	.09
J score > 3	192 (45%)	129 (38%)	63 (74%)	.001
Data are expressed as no. (%) or mean ± standard deviation.

Procedural details are shown on table 3. The use of 8-Fr catheters and dual injections was significantly higher among successful cases with a strong trend towards retrograde approach and intravascular ultrasound guidance. Drug-eluting stents were deployed in most of cases and limus-eluting stents were the most widely used by far (79%). PCIs were performed on at least 1 additional vessel in about two-thirds of the patients from the 2 groups. Independent predictors of failure were previous CABG, moderate-to-severe lesion tortuosity, tandem occlusions, lack of dual injection, and CTOs diagnosed in the ACS setting (table 4).

Table 3. Procedural characteristics

	All (n = 424)	Success (n = 339)	Failure (n = 85)	P
Femoral access	265 (63%)	215 (63%)	50 (59%)	.39
8-Fr catheter	207 (49%)	175 (52%)	32 (38%)	.03
Dual injection	367 (87%)	302 (89%)	65 (76%)	.02
Intervention
Drug-eluting stent		294 (87%)	NA
Bare metal stent		20 (6%)	NA
Drug-eluting and bare-metal stent		15 (4%)	NA
Balloon		10 (3%)	1 (1.2%)
Retrograde approach	94 (22%)	69 (20%)	25 (29%)	.07
IVUS	61 (14%)	56 (17%)	5 (6%)	.06
Duration (min)	105 ± 41	106 ± 42	102 ± 39	.43
Fluoroscopy dose (cGy/m²)	26 037 ± 2066	26 403 ± 2222	24 867 ± 13 019	.57
Contrast volume (mL)	367 ± 175	377 ± 177	327 ± 158	.002
IVUS, intravascular ultrasound. Data are expressed as no. (%) or mean ± standard deviation.

Table 4. Multivariate predictors

Failed procedure	HR	HR	P
Previous CABG	7.51	2.83-19.90	.0001
Moderate-to-severe tortuosity	3.78	2.02-7.08	.0001
ACS setting	2.42	1.26-4.61	.008
Tandem occlusion	2.32	1.11-4.87	.027
Lack of dual injection	2.43	1.14-5.55	.027
Cardiovascular mortality	HR	HR	P
Renal failure (< 60 mL/min)	5.67	1.95-16.48	.002
LAD occlusion	3.30	1.12-9.74	.032
Failed procedure	7.14	2.44-20.0	.0001
ACS, acute coronary syndrome; CABG, coronary artery bypass graft; LAD, left anterior descending coronary artery.

Twenty-six coronary dissections (6.2%) and 21 femoral hematomas (5%) were the most common procedural complications of all. In the course of the attempts, perforations occurred in 5 successful cases (1.5%) and in 9 failed cases (10.8%). However, emergent pericardiocentesis due to cardiac tamponade was required in 1 patient only. Contrast-induced nephropathy occurred in 8 successful cases (2.5%) and in 1 failed case (3.1%). One patient died during hospitalization due to cardiogenic shock that occurred 24 hours after a failed CTO attempt.

The differences seen among the 3 time periods led us to think that procedural technical advances, the operator’s increasing skills, and the improvements made in the assessment of the patients’ profile and selection of the lesions, contributed to the 87% rate of success reported at the final time frame. The temporal trends shown on table 5 describe the techniques developed in each corresponding period, not that all procedures were performed with that technique. Since June 2013 numerous cases have been successfully completed using the dissection/re-entry technique.The median follow-up was 39.7 months [22–102]. Follow-up information was available in 407 patients (99.8%). Clinical outcomes during follow-up are shown on table 6.

Table 5. Temporal trends in baseline angiographic characteristics, procedural data, and results

	1st period (2002-2007)	2nd period (2007-2011)	3rd period (2011-2017)	Total	P
Age	62 ± 16	63 ± 11	64 ± 11	63 ± 12	NS
Multivessel disease	61.7%	60.1%	82%	70%	.0001
ACS setting	36.1%	21.8%	23.6%	24.3%	.025
Previous CABG	9.8%	10.0%	3.9%	7.3%	.020
LAD	27.9%	33.3%	28.5%	30.4%	NS
Length (mm)	23 ± 14	22 ± 13	21 ± 18	23 ± 16	NS
J score > 3	45.0%	44.8%	45.8%	45.2%	NS
Rentrop grade 3 cc.	44.8%	62.8%	39.4%	48.6%	.0001
Femoral access	49.2%	68.0%	62.6%	62.5%	.016
8-Fr catheter	11.7%	58.3%	54.3%	48.8%	.0001
Dual injection	65.0%	90.1%	92.1%	86.5%	.0001
Retrograde approach	1.6%	23.3%	28.8%	22.1%	.0001
IVUS	21.2%	18.3%	11.1%	14.4%	.033
Fluoroscopy time (cGy/m²)	33245	30310	19830	26037	.0001
Contrast volume (mL)	453 ± 208	434 ± 178	281 ± 127	367 ± 175	.0001
Success rate	57%	81%	87%	80%	.001
More widely used wires	Polymer coated wires (Whisper ES or MS, Pilot 50, 150 or 200, Abbott Vascular, United States) and tapered, stiff wires (Confianza Pro 12, Asahi Intecc., Japan). Used in 58%.	Runthrough wire (Terumo, Japan) and nontapered, stiff wires (Miracle 3 or 6 and Ultimate Bross 3, Asahi Intecc., Japan). Used in 62%.	Runthrough and nontapered, stiff wires widely used (59%). Sion and Gaia wires (Asahi Intecc., Japan) were used in 21%.
Specific devices and techniques	Antegrade approach only. Parallel and seesaw wiring techniques.	Retrograde approach, Corsair specific catheter (Asahi Intecc., Japan) and Guideliner (Vascular Solutions, United States). Kissing and reverse CART techniques.	Double lumen Nhancer catheter (Interventional Medical Device Solutions, The Netherlands). Hybrid techniques with the CrossBoss and Styngray catheters (Boston Scientific, United States).
ACS, acute coronary syndrome; CABG, coronary artery bypass graft; ES, extra support; IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; MS, medium support.

Table 6. Clinical outcomes at follow-up

	All (n = 424)	Success (n = 339)	Failure (n = 85)	P
Overall mortality	64 (15.1%)	40 (11.8%)	24 (28.2%)	.001
Cardiovascular mortality	24 (5.7%)	12 (3.6%)	12 (14.1%)	.001
Myocardial infarction	10 (2.4%)	8 (2.4%)	2 (2.4%)	.99
Target vessel revascularization	45 (10.6%)	34 (10.1%)	11 (12.9%)	.44
Target lesion revascularization	40 (9.5%)	31 (9.2%)	9 (10.6%)	.69
CTO stent thrombosis
Definite		5 (1.5%)	NA
Probable		1 (0.3%)	NA
MACE	68 (16.1%)	47 (13.9%)	21 (24.7%)	.0015
CTO, chronic total coronary occlusion; MACE, major adverse cardiovascular events (cardiovascular death, myocardial infarction or need for surgical or percutaneous target vessel revascularization). Data are expressed as no. (%).

In the success group, 33 restenosis (9.7%) were angiographically diagnosed, 42% of which ended up being occlusive. Target lesion revascularization was achieved in 31 of these restenotic lesions (9.2%). Four of the 5 cases of definite thrombosis corresponded to a successfully opened right coronary artery.

One case of severe radiodermatitis was identified and it was successfully treated with local surgery 6 years after the intervention.

A remarkable difference in MACE was observed in favor of the success group, mainly driven by a lower rate of cardiovascular mortality. The cumulative cardiac survival and MACE survival curves associated with the success or failure of the PCI are shown on figure 2 and figure 3.

Figure 2. MACE-free at the 5-year follow-up. The rate of MACE (cardiovascular death, infarction, and surgical or percutaneous TVR) was lower in successful cases (P = .03).
MACE, major adverse cardiovascular events (cardiovascular death, myocardial infarction or need for surgical or percutaneous TVR); TVR, target vessel revascularization.

Figure 3. Cardiovascular mortality-free at the 5-year follow-up. Significant lower cardiovascular mortality in the success group (P = .005).

The multivariate analysis confirmed that a past medical history of chronic kidney disease with creatinine clearance < 60 mL/min, LAD occlusions, and procedural failure were independent predictors of cardiovascular mortality (table 4). Actually, increased mortality-related success rates were only seen in cases of failed LAD-CTO recanalization attempts compared to failed non-LAD CTO attempts (35% vs 9% P = .012).

DISCUSSION

These are the main results of this registry: a) the higher rates of success seen over the last 15 years confirm the improvements made in CTO recanalization devices and in the operator’s skills; b) the recanalization of CTOs shows high rates of success (80.0%) and low rates of complications; c) the rates of success were significantly lower in patients with previous CABG, moderate-to-severe lesion tortuosity, tandem occlusions, lack of dual injection, and patients with CTO treated in the ACS setting; d) successful procedures, especially in LAD occlusions, were associated with lower rates of cardiovascular mortality and MACE at the long-term follow-up.

The recanalization of the CTO is still uncertain and is not yet supported by randomized clinical trials. Several retrospective observational studies8^-10 provide evidence that support this strategy. The results found in this analysis are consistent with previously published data, but disagree with others.11^,12. In this sense, the more recent registries show better results regarding cardiovascular and overall mortality.13^,14

Regarding randomized clinical trials, the EUROCTO trial revealed that the PCI of a CTO improves health status with improvements in angina frequency in patients with stable angina.15 However, the EXPLORE trial did not reveal any differences in the left ventricular function of patients with ST-segment elevation myocardial infarction. The DECISION-CTO showed similar inter-group rates of death, MI, stroke or TLR in patients with ACS or stable angina at the 3-year follow-up.16^,17 The most recent clinical trial (REVASC) did not show an improved regional myocardial function. Although it was underpowered to measure clinical outcomes, it showed the advantage of performing the PCI of a CTO for clinically-driven repeat revascularization.18

Several characteristics of the current study should be emphasized to put the results into perspective. We believe this series of CTOs to be the big picture of interventional cardiology regarding CTOs since the start of the drug-eluting stent era until the arrival of contemporary new technologies. The study is based on a large cohort of consecutive patients from a single center. Most of them had multivessel disease and were treated in different time frames according to a specific dedicated CTO program.

Among the procedural characteristics that could explain the lower rates of success obtained with CTOs in the ACS setting we found the lowest use of retrograde approach and 8-Fr catheters in non-adequately staged procedures.

Regarding procedural features, the use of IVUS was limited to cases that required assessment of the distal vessel diameter and to optimize procedures with severe calcifications. It is very likely that more IVUS-guided procedures should have been performed.

Regarding variables related to procedural outcomes in the multivariable analysis, previous CABGs and more complicated CTOs were associated with failure as shown by other registries.13 However, intralesional tortuosity seems to us like the most consistent multivariable predictor with greater contribution to the model due to its narrow confidence interval. It might be possible that the inclusion of several angiographic variables in the regression model is responsible for the J-score not becoming an independent predictor. The high rate of retrograde procedures reveals the complexity of the CTOs in our series with J score > 3 in 45% of cases.

After dividing the series into 3 different periods of time, significant improvements in the rates of success were emphasized. As a result, we saw some interesting changes over time, such as the contribution of the retrograde approach to success. Considering that 73% of retrograde procedures were successful, it can be said that this technique led to a 19% increase in the rates of success in absolute terms. The rate of complications was quite similar to that from other studies.2^-4^,8^-14

Our data provide additional evidence on the lower rate of cardiovascular mortality reported in patients with successful CTO recanalization in the long-term follow-up. As a matter of fact, the success of the PCI was a strong independent predictor of survival as several observational studies and 1 meta-analysis have consistently suggested.13^,14^,19

Possible explanations of the survival benefit from revascularizing a CTO may include a better left ventricular function and more tolerance for future acute coronary occlusive events.20 However, this cannot be confirmed as we didn’t measure the left ventricular ejection fraction systematically during follow-up. However, the trend showing a worst clinical profile in failed CTOs would validate this statement.

The role of LAD occlusions is decisive, as it seems an independent predictor of mortality. It should be mentioned that this effect of LAD occlusions on cardiovascular mortality was basically due to the higher mortality rate of failed cases compared to LAD recanalization attempts. The fact that LAD CTOs are much easier to open than CTOs located in other vessels makes LAD attempts not only feasible but also mandatory.

In conclusion, we think that this study —performed in a contemporary single cardiac catheterization laboratory for a long period of time practice in the drug eluting stent era— features new information on procedural results and long-term outcomes on CTO recanalizations.

This study was a prospective analysis and is subject to the limitations inherent to this type of research. The study does not allow us to draw any comparisons with other therapeutic strategies like medical therapy or CABG. Patients with failed procedures had different clinical and angiographic characteristics, which may have impacted prognosis.

Angiographic characteristics were not analyzed in a core lab but provided by a local investigator. There was no adjudication of clinical outcomes by a clinical events committee.

CONCLUSIONS

The implementation of a specific PCI program for CTOs has been associated with higher rates of success over time thanks to growing expertise and new technical advances. The rate of procedural success was lower when there was a history of previous CABG, moderate-to-severe lesion tortuosity, tandem occlusions, lack of dual injection, and in CTOs diagnosed in the ACS setting. Preserved renal function and successful recanalization —especially of the LAD— were associated with a lower rate of cardiovascular mortality in the long-term follow-up.

CONFLICTS OF INTEREST

J.M. de la Torre is the Editor-in-chief of REC: Interventional Cardiology; the editorial procedure established by REC: Publications was followed to guarantee the fair and unbiased handling of the manuscript.

 

 

REFERENCES

INTRODUCTION

Percutaneous coronary intervention (PCI) in calcified coronary lesions is often challenging and may be associated with suboptimal stent expansion and apposition both related to stent failure due to stent thrombosis and in-stent restenosis.1^-3 The balloon angioplasty used in calcified lesions increases the risk of dissection of non-calcified segments usually without significant modification of calcified plaques and often without a proper luminal gain.4 The management of this subset of lesions is complex and often requires complex techniques such as rotational atherectomy or excimer laser coronary atherectomy.

Intracoronary lithotripsy (ICL) (Shockwave Medical, Freemont, CA, United States) has emerged as a new tool to modify calcium by applying a diffuse acoustic pulse through a balloon inflated at 4 to 6 atmospheres without damage to endovascular soft tissues. The multicenter, prospective, single-arm Disrupt CAD II clinical trial5 has recently evaluated the safety and feasibility of the ICL system prior to stent implantation in 120 patients with coronary artery disease and calcified coronary lesions. This study showed that the ICL appeared feasible with favorable initial success and complication rates in selected patients.5 Although its use has grown rapidly among interventional cardiologists and there are many case reports on the medical literature available to us, the experience already reported on this new device is quite limited. We present the initial results of lithotripsy-assisted PCIs in a real-life cohort of high-risk patients with complex, calcified lesions.

METHODS

Patient population and data collection

Two-center, prospective, observational registry including all consecutive PCI cases that required ICL prior to stent implantation to the operator’s discretion from October 2018 to March 2019. The baseline characteristics and procedural and in-hospital outcomes were prospectively recorded.

Intracoronary lithotripsy procedure

The ICL system is a portable and rechargeable generator connected to the ICL catheter. The catheter consists of a rapid exchange semi-compliant 12-mm balloon with 2 radiopaque emitters mounted inside available in 2.5, 3.0, 3.5, and 4 mm diameters. The catheter is compatible with a 6-Fr guiding catheter with a crossing profile range of 0.042 in and it is placed across the calcified lesion through a 0.014 in guidewire. Once in position, the balloon is inflated at 4 atmospheres to make intimate contact with the vessel wall and facilitate an efficient the transfer of energy. An electrical discharge from the emitters vaporizes the fluid inside the balloon generating sonic pressure waves that create a localized field effect. The ICL catheter is connected to a generator preprogrammed to deliver 10 pulses at a rate of 1 pulse per second. Each catheter can administer a maximum of 80 pulses. The sonic pulses through the soft vascular tissue cause selective microfractures at the intimal and medial calcium level of the vessel wall. After the pulse emission and the corresponding modification of calcium, the balloon is inflated up to 6 atmospheres to maximize luminal gain.

Definitions and outcomes

The use of the ICL catheter was based on the presence of a significant and severely calcified lesion (70% stenosis in an epicardial coronary vessel) on the angiography or intravascular imaging.

Coronary calcified lesions were defined by: a) the presence of radiopacities prior to contrast injection often involving both sides of the arterial wall; b) the presence of ≥ 270 degrees of calcium on at least one single cross-section on the intravascular ultrasound or optical coherence tomography (OCT); or c) subsets of calcified lesions with previous failed revascularization attempts.

According to the Disrupt CAD II trial criteria,5 lithotripsy delivery was considered successful when it facilitated stent delivery with < 50% residual stenosis and without any serious angiographic complications like severe dissection, perforation, slow flow or persistent no-reflow. In addition, clinical success was defined as residual stenosis < 50% after stenting without any evidence of in-hospital adverse events. We also assessed procedural complications such as PCI-related myocardial infarction (type 4a myocardial infarction, defined according to the fourth universal definition of myocardial infarction),6 and in-hospital and 30-day outcomes.

Statistical analysis

Categorical variables were expressed as number (percentage) and continuous variables as mean ± standard deviation or median according to their distribution. We analyzed all data using the STATA statistical package version 15.0 (StataCorp LP, College Station, Texas, United States).

RESULTS

Patients

Between October 2018 and March 2019, 25 patients with 37 calcified lesions were treated, which amounted to 2.7% of the patients treated with PCIs in both centers. The baseline characteristics of the patients are shown on table 1. Mean age was 71 ± 9 years and 68% of the patients were males. The traditional cardiovascular risk factors were common and the vast majority of patients had undergone a previous revascularization (PCI or coronary artery bypass graft). The indication for PCI was acute coronary syndrome in most cases (76%), all of them non–ST-elevation myocardial infarctions.

Table 1. Baseline characteristics (per patient)

Clinical characteristics	N = 25
Age, years	71 ± 9
Male sex	17 (68)
Diabetes	17 (68)
Renal failure	7 (28)
Peripheral vascular disease	8 (32)
Previous PCI	14 (56)
Previous CABG	3 (12)
LVEF	49 ± 17
ACS on admission	19 (76)
ACS, acute coronary syndrome; CABG, coronary artery bypass graft; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention. Data are expressed as no. (%) or mean ± standard deviation.

Procedural characteristics

Procedural characteristics are shown on table 2. The mean SYNTAX score (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) was 19.3 ± 2, and the left anterior descending artery was the most-treated vessel. A non-negligible proportion of complex coronary artery lesions like chronic total coronary occlusions (CTO), bifurcation and ostial lesions, and stent underexpansion were also treated.

Table 2. Procedural characteristics

Lesion characteristics	N = 37
Protected LMCA	1 (3)
Unprotected LMCA	4 (11)
LAD	17 (46)
LCx	3 (8)
RCA	12 (32)
Syntax Score	19.3 ± 2
Stent underexpansion treatment	4 (11)
Ostial lesions	13 (35)
Bifurcation lesion	13 (35)
CTO	3 (8)
Lesion severity by QCA	N = 37
Pre-PCI diameter stenosis	81.6 ± 2.5
Post-PCI diameter stenosis	15.9 ± 3.4
Pre-PCI area stenosis	84.6 ± 3.8
Post-PCI area stenosis	21.6 ± 3.5
Total lesion length, mm	20.7 ± 3
Mean luminal diameter, mm	0.77 ± 0.1
Procedural characteristics	N = 25
Radial access	15 (60)
Mechanical support Impella device	5 (20)
Fluoroscopy time, min	31.5 ± 4.8
Contrast, mL	212 ± 28
Number of vessels treated (per patient)	1.3 ± 0.5
Number of lesions treated (per patient)	1.7 ± 0.8
PCI characteristics	N = 37
Pre-ICL balloon pre-dilatation	23 (62)
Pre-ICL rotational atherectomy	10 (27)
Pre-ICL cutting balloon	2 (5)
ICL number of pulses	46 ± 19
ICL balloon rupture	3 (8%)
Number of stents implanted	1.2 ± 0.6
Stent diameter, mm	3.3 ± 1
Stent length, mm	23.1 ± 10
Angiographical success	35 (95)
CTO, chronic total coronary occlusion; ICL, intracoronary lithotripsy; LAD, left anterior descending coronary artery; LCx, left circumflex artery; LMCA, left main coronary artery; PCI, percutaneous coronary intervention; QCA, quantitative coronary angiography; RCA, right coronary artery. Data are expressed as no. (%) or mean ± standard deviation. The ICL was used after a failed attempt of balloon pre-dilatation in 62% of the lesions, of which 10% showed balloon rupture. Ten lesions (27%) had previously been treated with rotational atherectomy. Only one lithotripsy catheter per lesion was required, and the mean number of pulses was 46 ± 19. The crossing rate of the lithotripsy balloon was 100% in pre-dilated and non-pre-dilated lesions, and the ICL balloon rupture occurred in 3 cases (8%) with no associated complications. An OCT prior to the ICL therapy was performed in a small percentage of cases (10%) to the operator’s discretion. All stents implanted were drug-eluting stents and successful angiographic result according to the definition was achieved in 95% of cases.

Intracoronary lithotripsy in complex lesions

A subset of complex lesions was also treated with lithotripsy balloon (table 2). Success rate was 100% for left main coronary artery revascularizations, 100% for CTOs, and 86% for bifurcations.

Left main coronary artery lesions

Five patients with left main coronary artery lesions were treated with the ICL balloon. Four were unprotected lesions and were treated under hemodynamic support using the Impella device (all of them showed a severely depressed ejection fraction and/or a right coronary artery chronic total occlusion). Device and clinical success were achieved in all cases.

Bifurcation lesions

Seven lesions treated involved bifurcations, 4 were treated using a provisional stenting technique, and 3 cases were treated using the 2-stent technique (V stenting).

Chronic total coronary occlusions

The CTOs of 3 patients were treated using the ICL with complete success in all of them. The first patient had a severely calcified aorto-ostial lesion in the right coronary artery, a Japanese chronic total coronary occlusion score (Japanese Multicenter CTO Registry) of 2 (presence of calcification ≥ 20 mm in length). After unsuccessful pre-dilation using 2 balloons (1 of them ruptured) the ICL was performed and good balloon expansion was achieved without need for post-dilatation prior to the stenting. The second successfully treated CTO case involved the mid portion of the left anterior descending coronary artery (bifurcation according to the Medina classification 1,1,1), Japanese CTO score of 2 (calcification ≥ 20 mm in length) that had been treated with rotational atherectomy prior to the ICL. The third case was the CTO of a distal right coronary artery involving bifurcation (according to the Medina classification 1,0,0) and a Japanese CTO score of 3 (blunt-tip entry, calcification ≥ 20 mm in length). The artery was dilated using 5 balloons, some of which ruptured before performing the ICL. Lesion expansion was completed with a cutting balloon after the ICL, which allwed proper stent implantation.

Stent underexpansion

Four cases of stent underexpansion were treated, but results after the ICL were only successful in one case. There was 1 case that needed additional very high-pressure balloon dilatation (up to 40 atmospheres) for proper expansion, and 2 cases that remained unexpanded even after very high-pressure balloon dilatation (up to 40 atmospheres), and in-stent rotational atherectomy with 1.75 and 2.00 mm burrs.

In-hospital and 30-day outcomes

The procedure was performed safely in all cases. Both the clinical and device success were high with no in-hospital mortality. One patient died of non-cardiac causes at the 30-day follow-up (sepsis due to spontaneous bacterial peritonitis in the presence of hepatic cirrhosis). Procedural, in-hospital, and 30-day outcomes are shown on table 3.

Table 3. In-hospital and 30-day outcomes

Clinical outcomes	N = 25
Procedural complications
Dissection	0 (0)
Perforation	0 (0)
No-reflow	0 (0)
Type 4a acute myocardial infarction	3 (12)
In-hospital mortality	0 (0)
30-d myocardial infarction	0 (0)
30-d target-vessel revascularization	0 (0)
30-d stent thrombosis	0 (0)
30-d mortality	0 (0)
Cardiac death	0 (0)
Non-cardiac death	1 (4)
Data are expressed as no. (%) or mean ± standard deviation.

DISCUSSION

We present our initial experience with ICL in a cohort of real-life clinically complex patients with heavy coronary artery calcification and showed that the ICL is feasible with favorable initial outcomes and low complication rates.

Debulking techniques like rotational atherectomy, orbital atherectomy or excimer laser coronary atherectomy are commonly used to treat calcified coronary lesions. Back in 2018, in Spain up to 1517 patients were treated with rotational atherectomy and 88 with excimer laser coronary atherectomy.7 Recently, the ICL has emerged as an attractive option for the management of patients with severely calcified coronary lesions. Nevertheless, the experience reported on this new technique is still limited. The recently published single-arm Disrupt CAD II clinical trial confirmed the safety and performance of ICL to treat calcified coronary lesions.5 However, the clinical characteristics of the patients enrolled in this trial show a relatively low-risk population. Complex calcified coronary lesions are a common thing and they amount to 25% to 30% of all PCIs performed.3 Among our population, 2.7% of patients were considered eligible to receive ICL therapy, indicative of a highly demanding indication criterion. Compared to the Disrupt CAD II clinical trial5 our patients were younger but had a worse clinical scenario with a higher prevalence of diabetes (68% vs 32%) and renal failure (22% vs 9%), and up to 76% had suffered an acute coronary syndrome (none in the Disrupt CAD II trial). Another recent report described the initial experience with ICL in a cohort of 26 patients with calcified coronary lesions with findings for the clinical characteristics and results similar to the Disrupt CAD II.8

Regarding the procedure, it should be noted that the crossing rate for the ICL balloon was 100% despite a high percentage of plaque preparation was required (62% balloon pre-dilatation, 27% rotational atherectomy). Recently, the combination of rotational atherectomy and ICL has been described as RotaTripsy, suggestive that these 2 calcium debulking techniques may be complementary, since rotational atherectomy facilitates the ICL balloon crossing, and the latter facilitates proper expansion in the presence of circumferential deep calcium plaques.9 The device success rate was 84% (100% in the Disrupt CAD II linical trial) and the clinical success rate was 95% (94% in the Disrupt CAD II trial). And most important of all, no major procedural complications were seen, which is consistent with the Disrupt CAD II trial results. The rupture of the ICL balloon during inflation occurred in 3 cases (12%) without associated complications, yet the rupture of the balloon has been described in a case report resulting in a type C coronary dissection; the interventional cardiologist needs to be aware of this lithotripsy-related potential complication.10 Intra­vascu­lar imaging were performed in few cases probably because the operator thought it would be difficult to cross an especially severe and calcified lesion with the OCT or IVUS catheter. Consistent with the results of the Disrupt CAD I and II clinical trials and OCT substudy,5^,11 it was confirmed that the modification of calcium and the presence of fractures lead to an acute area gain and favorable stent expansion in the lesions assessed through OCT in our series. Figure 1 shows the coronary angiography and OCT of one complex patient treated with ICL; the red arrows seen on figure 1D,E indicate calcium fractures after the ICL.

Figure 1. Intracoronary lithotripsy, angiography, and optical coherence tomography. Patient with severe coronary artery heart disease with severely depressed left ventricular ejection fraction previously treated with coronary artery bypass graft (venous graft-left anterior descending coronary artery, currently occluded). Treatment of left main coronary artery, left anterior descending artery, and diagonal branches. A: pre-intracoronary lithotripsy angiography. B: Impella-assisted PCI of left anterior descending coronary artery. Arrow indicates inflated lithotripsy balloon. C: successful final angiographic result after stenting. D, E and F: optical coherence tomography cross-sectional images of a post-lithotripsy calcified lesion. Red arrows indicate calcium microfractures after intracoronary lithotripsy.

We used the ICL in a subset of highly complex lesions like left main coronary artery stenosis, CTO, stent underexpansion, and bifurcation lesions.

Five complex patients with calcified left main coronary artery and severe stenosis were treated with ICL; mechanical support with the Impella device was needed in 4 patients due to a depressed left ventricular ejection fraction. Recently, a case report with 2 patients that were successfully treated with ICL in a left main coronary artery stenosis has also been published.12 The ICL seems like a safe treatment option to treat calcified left main coronary artery stenoses even in technically complex cases that require hemodynamic support, a clinical scenario where the use of rotational atherectomy or excimer laser coronary atherectomy is rare.

Three patients with CTO lesions were successfully treated with ICL. Treatment of CTO with ICL has been previously described in 2 case reports. The first one was a patient with a CTO in the proximal right coronary artery. In this case, the ICL allowed the reverse controlled antegrade/retrograde tracking at the location of heavy calcification at the site of the chronic occlusion.13 The second case was a patient with a proximal right coronary artery CTO due to heavily calcified in-stent restenosis. The ICL achieved good lesion expansion prior to stent implantation.14 If performed properly, the ICL can be an alternative to other debulking techniques in heavily calcified CTO lesions to guarantee proper lesion expansion.

Several case reports of stent underexpansion due to heavily calcified lesions successfully treated with ICL have been reported recently.15^,16 Surprisingly, in our series the ICL failed to achieve proper stent expansion in 3 out of the 4 cases attempted. The management of stent underexpansion using ICL should be performed with extra caution because sound waves can damage the metallic structure of the stent.

The management of calcified bifurcation lesions is often complex due to the high risk of side branch occlusion when applying debulking techniques such as rotational atherectomy or excimer laser coronary atherectomy because the treatment cannot be performed using a guidewire for side branch protection purposes.17^,18 The ICL allows us to treat the main branch bifurcation with a guidewire in the side branch to guarantee quick access in case of flow impairment just like conventional procedures do.

Compared to atherectomy or specialty balloons, the ICL is said to offer several potential advantages5 and requires no specific training as the device is delivered similar to the standard catheter-based PCI. ICL therapy is balloon based, and, therefore, the risk of athero­matous embolization may be lower compared to free debulking devices; according to the Disrupt CAD I (19) or Disrupt CAD II trial5 results, none of the patients from our series experienced no-reflow events and the rate of periprocedural myocardial infarction was relatively low. Whereas standard and specialty balloons are inflated at high atmospheric pressure to modify calcium, the ICL is typically performed at low atmospheric pressure balloon inflation, thus minimizing mechanical vascular trauma. Lastly, side-branch protection using a guidewire may be easily performed using ICL, without running the risk of wire entrapment or severing associated with rotational or orbital atherectomy. However, there is no evidence regarding stent restenosis of lesions treated with ICL therapy. New studies like the Disrupt CAD III trial that has just begun and will be recruiting up to 400 patients with a 2-year follow-up are needed to determine long-term outcomes.

Limitations

This 2-center experience using the ICL balloon has the limitations inherent to an observational study with a small sample size, which limits drawing conclusions especially in subgroups of high-risk lesions treated with ICL. However, in our opinion, it may contribute by adding more evidence supporting the use of ICL. This study did not have a comparison group either among existing plaque-modifying techniques.

CONCLUSIONS

In our own experience, the ICL-enhanced PCI was performed safely and effectively in a real-life cohort of complex patients with severely calcified and highly complex lesions.

CONFLICTS OF INTEREST

The authors of the manuscript declared no conflicts of interest.

 

REFERENCES

INTRODUCTION

Coronary angiography (CA) is a key step in treatment of patients with non-ST-elevation acute myocardial infarction (NSTEMI). CA reduces mortality and the rates of new cardiovascular adverse events compared to the conservative approach.1^,2 Therefore, the current European clinical practice guidelines on the management of NSTEMI recommend an invasive strategy to treat these patients.1

The appropriate time to perform the CA in NSTEMI patients is still under discussion. Early CA (within the first 24 h after diagnosis) is still recommended in patients with high-risk NSTEMI defined as a GRACE score > 140. However, the potential benefit of this approach has not been completely established yet.3

The objective of our study was to assess the prognostic impact of an early CA (within the first 24 h after diagnosis) in patients NSTEMI compared to a delayed CA strategy (after 24 h).

METHODS

This is a retrospective, observational cohort study. From January 2014 to June 2016, data from 447 patients with NSTEMI admitted to a tertiary referral hospital who underwent an invasive coronary angiography were consecutively collected.

NSTEMI was defined according to the guidelines and all patients were treated following the recommendations established by these guidelines.1

Data from all the cases were included prospectively in a continuous multipurpose database. The collection of data included detailed past clinical histories, physical examinations, pulse oximetry measures, 12-lead electrocardiograms, continuous electrocardiogram monitoring, blood tests, echocardiographies, and CAs. The Global Registry of Acute Coronary Events (GRACE) and Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) scores were calculated for each patient.1

Patients were classified into 3 groups according to the time to CA (figure 1): catheterization within the first 24 h after diagnosis (group 1, n = 285 patients), 24 h to 72 h later (group 2, n = 102 patients) and after 72 h (group 3, n = 60 patients). The decision on when to perform the CA was made by the treating physician in each case. After being discharged from the hospital, the 12-month follow-up of patients was performed in a dedicated clinic.

Figure 1. Flowchart. CA, coronary angiography; NSTEMI, non-ST-elevation acute myocardial infarction.

The primary endpoints of our study were mortality and major adverse cardiovascular events (stroke, new acute coronary syndrome, new revascularization) during hospitalization and depending on the time to CA in patients with NSTEMI. The secondary endpoints were mortality and the rate of major cardiovascular events at the 1-year follow-up, and bleeding events according to the BARC criteria.4 We also analyzed the antiplatelet treatment prescribed at discharge and its correlation with MACE at follow-up.

Statistical analysis

Continuous variables are described as mean and standard deviation or median and interquartile range [IQR] when appropriate. The Kolmogorov-Smirnov test was used to assess the variables normal distribution. Regarding quantitative variables, the groups were compared using the 2-tailed Student t test or the Mann-Whitney U test when necessary. Categorical variables were expressed as frequency and percentage, and compared using the chi-square test or Fisher’s exact test when appropriate. No variable had losses > 15%.

A multivariate logistic regression analysis was performed to assess the potential impact of the CA timing on in-hospital mortality. The model included all variables that were statistically significant in the univariate analysis regarding mortality and time to CA. Adjusted odds ratios (OR) with 95% confidence intervals (95%CI) were calculated for each variable. Regarding the secondary endpoint of 1-year mortality, a Cox regression analysis was performed to assess any potential prognostic factors.

All tests were 2-tailed and the differences were considered statistically significant with P values < .05. The statistical analysis was performed using the statistical software package IBM SPSS Statistics V 22.0.

RESULTS

Table 1 shows the baseline characteristics of the patient population. Patients in group 1 were younger (66.5 ± 13.5 years vs 71.1 ± 12.7 years in group 2, and 70.7 13.5) in group 3, P = .016). There were no gender differences among the groups (P = .565). The cardiovascular risk factors, previous coronary artery disease (P = .314), and presence of other comorbidities were similar among the groups (table 1).

Table 1. Baseline characteristics among the 3 study groups and antiplatelet therapy at discharge

	Group 1 (n = 285)	Group 2 (n = 102)	Group 3 (n = 60)	P
Age (years)	66.5 (13.5)	70.7 (13.5)	71.1 (12.7)	.016
Sex (male)	78.9%	80.2%	73.3%	.565
Diabetes	34.9%	37.6%	35.0%	.880
Hypercholesterolemia	63.4%	54.5%	55.9%	.195
Hypertension	71.1%	71.3%	73.3%	.942
GRACE score	157 (44.9)	161 (45.7)	170 (39.6)	.041
CRUSADE score	32.8	34.8	36.4	.251
GFR	72	69.8	66	.118
Peak CK levels	659.9	479.4	590	.623
LVEF at discharge	49.6	54.2	52	.229
Killip class	.604
I	194 (71.3%)	75 (72.7%)	37 (62.7%)
II	32 (11.8%)	15 (15.2%)	9 (15.3%)
III	23 (8.5%)	7 (7.1%)	8 (13.6%)
IV	23 (8.5%)	5 (5.1%)	5 (8.5%)
Mechanical ventilation	29 (10.7%)	6 (6.1%)	5 (8.3%)	.636
Number of vessels with severe stenosis	.488
1	133 (46.8%)	45 (44.6%)	23 (38.6%)
2	77 (27.1%)	23 (22.8%)	22 (36.7%)
3	68 (23.9%)	29 (28.7%)	14 (23.3%)
Successful revascularization	211 (89.8%)	70 (92.1%)	42 (91.3%)	.930
Antiplatelet therapy at discharge
Ticagrelor	154 (54%)	52 (50.9%)	29 (48.3%)	.154
Clopidogrel	105 (36.8%)	40 (39.2%)	24 (40%)	.358
Prasugrel	26 (9.2%)	10 (9.9%)	7 (11.7%)	.469
CK, creatine kinase; GFR, glomerular filtration rate; LVEF, left ventricular ejection fraction. Group 1: coronary angiography within the first 24 h after diagnosis; group 2: 24 h to 72 h later; group 3: coronary angiography > 72 h after diagnosis.

A CA was performed within the first 24 h in 285 patients (63.8%). Surprisingly, we noticed that the patients from group 1 showed lower GRACE scores [157.67 (44.9) points vs 170 (39.5) points in group 3, (P = .041)] and similar CRUSADE scores compared to the other 2 groups (P = .251).

There were no significant differences among the groups in the Killip class at admission (table 1). The left ventricular ejection fraction and the peak values of cardiac biomarkers were similar among the groups. The presence of multivessel disease was similarly in the 3 study groups (table 1). There were no significant differences in the primary endpoint among the 3 study groups (table 2). During hospitalization, strokes and bleeding events occurred similarly in the 3 groups (table 2). It is important to emphasize here the low rate of bleeding events (5 patients with BARC 2 and 2 patients with BARC 3 events in group 1, and 3 patients with BARC 2 and 2 patients with BARC 3 events in groups 2 and 3, with no fatal events). At the 1-year follow-up, cardiovascular adverse events and 1-year mortality were similar among the 3 groups (table 2).

Table 2. In-hospital and follow-up rate of adverse events and mortality (expressed as percentage) among the 3 groups

	Group 1 (n = 285)	Group 2 (n = 102)	Group 3 (n = 60)	P
In-hospital events
Heart failure	74 (25.9%)	26 (25.4%)	21 (36%)	.246
Non-fatal AMI	3 (1%)	4 (3.9%)	3 (6%)	.371
Acute kidney injury	47 (16.5%)	18 (17.6%)	15 (25%)	.334
Stroke	3 (1%)	2 (1.9%)	2 (3.3%)	.548
Bleeding events	20 (7%)	6 (5.8%)	6 (10%)	.213
In-hospital mortality	19 (6.6%)	7 (6.8%)	2 (3.4%)	.358
Events at the 1-year follow-up
Death	17 (5.9%)	5 (4.9%)	5 (8.3%)	.114
Stroke	3 (1.05%)	3 (2.9%)	1 (1.6%)	.271
Major bleeding	7 (2.45%)	6 (5.8%)	4 (6.6%)	.427
Myocardial infarction	16 (5.6%)	5 (4.9%)	4 (6.6%)	.907
AMI, acute myocardial infarction. Group 1: coronary angiography within the first 24 h after diagnosis; group 2: 24 h to 72 h later; group 3: coronary angiography > 72 h after diagnosis.

Regarding medical treatment at discharge, a similar percentage of patients received clopidogrel, prasugrel and ticagrelor in the 3 study groups (table 1). In our cohort, antiplatelet therapy was not associated with differences in the rate of major adverse cardiovascular events and mortality at the 12-month follow-up.

The multivariate logistic regression analysis performed to predict mortality revealed that hypertension, Killip class IV at admission, left ventricular ejection fraction, and myocardial damage (defined as peak creatine kinase levels) were independently associated with higher in-hospital mortality rates. The time to CA was not an independent predictor of in-hospital mortality after the multivariate adjustment (table 3).

Table 3. Multivariate logistic regression analysis to predict in-hospital mortality

Variable	Odds ratio (95%CI)	P
CA after 72 h	reference
CA within the first 24 h	0.98 (0.26-3.74)	.978
CA 24 h to 72 h later	1.33 (0.28-6.24)	.716
Hypertension	6.25 (1.09-33.3)	.04
Age (per year)	1.03 (0.98-1.08)	.292
Successful revascularization	0.51 (0.12-2.21)	.371
Peak CK levels (per pg/mL)	1.00 (1.00-1.01)	.010
LVEF	0.93 (0.90-0.97)	< .001
Killip class at admission
I	reference	.026
II	3.39 (0.98-11.75)	.054
III	3.24 (0.92-11.36)	.067
IV	15.34 (2.19-107.58)	.006
95%CI, 95% confidence interval; CA, coronary angiography; CK, creatine kinase; LVEF, left ventricular ejection fraction.

Regarding 1-year mortality, the Cox regression analysis showed similar results. The time to CA was non-significant in the multivariate analysis. Hypertension, age, left ventricular ejection fraction, and Killip class at admission were independently associated with higher mortality rates at 1 year (table 4).

Table 4. Multivariate Cox regression analysis to predict 1-year mortality

Variable	Hazard ratio (95%CI)	P
CA after 72 h	reference
CA within the first 24 h	0.96 (0.46-2.03)	.919
CA 24 h to 72 h later	0.82 (0.33-2.07)	.677
Hypertension	3.64 (1.30-10.3)	.014
Age (per year)	1.04 (1.01-1.07)	.022
Successful revascularization	0.94 (0.41-2.13)	.876
Peak CK levels (per pg/mL)	1.00 (1.00-1.01)	.198
LVEF	0.96 (0.94-0.98)	< .001
Killip class at admission
I	reference
II	2.83 (1.32-6.08)	.008
III	2.78 (1.27-6.09)	.010
IV	2.91 (0.83-10.2)	.096
95%CI, 95% confidence interval; CA, coronary angiography; CK, creatine kinase; LVEF, left ventricular ejection fraction.

DISCUSSION

Our study included a large cohort of 447 consecutive patients with NSTEMI that were retrospectively analyzed. Our results showed that early CAs (defined as a CA performed within the first 24 h after diagnosis) in NSTEMI patients did not improve the prognosis of this cohort of patients compared to delayed CAs. No differences were seen among the 3 groups regarding the time to CA in the in-hospital cardiovascular adverse event rate, mortality rate or at the 12-month follow-up either.

Early CA, within the first 24 h after diagnosis, is currently recommended by the clinical practice guidelines for the management of patients with NSTEMI. However, this recommendation is based on the results of relatively old clinical trials and a meta-analysis.4^-8 Several recent trials have explored the prognostic impact of the CA timing on NSTEMI patients in order to find stronger evidence in this clinical setting.9^,10

The results of the TIMACS study (Timing of Intervention in Acute Coronary Syndromes) showed that an early CA was associated with a reduction in the composite endpoint of death, myocardial infarction or refractory ischemia compared to a delayed CA strategy.11

A retrospective cohort study that included 19 704 propensity scorematched patients hospitalized with a first acute coronary syndrome conducted between January 1, 2005 and December 31, 2011 showed that the use of an early invasive treatment strategy was associated with a lower risk for cardiovascular mortality and re-hospitalization due to myocardial infarction compared to a conservative invasive approach.12 However, it is important to emphasize the retrospective nature of this study and the fact that patients were followed for 60 days only.

However, a meta-analysis that combined data from 83 229 patients did not show any significant differences regarding mortality, myocardial infarction or major bleeding events between the 2 strategies.13

Another meta-analysis that included 8 randomized controlled trials (n = 5324 patients) with a median follow-up of 180 days [180-360] and compared an early invasive group of NSTEMI patients to a delayed strategy showed that the early invasive strategy did not reduce mortality in all NSTEMI patients including high risk patients with GRACE score > 140 points.14

Similarly, a recent meta-analysis that combined the results of 10 clinical trials did not find any differences in mortality, myocardial infarction or major bleedings among NSTEMI patients based on the CA timing. Nevertheless, the early CA strategy was associated with less recurrent angina and shorter hospital stays.15

The LIPSIA-NSTEMI study randomized patients with NSTEMI to undergo CA within the first 2 h after randomization (immediate CA strategy), 10 h to 48 h after randomization (early CA), and the so-called “selectively invasive” arm, in which patients initially received medical treatment without showing any differences in the infarct size among the 3 study groups.16

A recent randomized controlled trial conducted by a Kofoed et al., the VERDICT trial, included a total of 2147 patients of which 1075 were allocated to very early invasive evaluation (within the first 12 h after diagnosis), and 1072 to receive standard invasive care (CA 61.6 h after randomization).17 The primary endpoint was a composite of all-cause mortality, nonfatal recurrent myocardial infarction, refractory myocardial ischemia-related hospital admission or heart failure-related hospital admission. In this trial, the very early invasive coronary evaluation strategy did not improve overall the long-term clinical outcome compared to the invasive strategy performed within 2 to 3 days in patients with non-ST-segment elevation acute coronary syndrome. However, in patients with the highest risk, the very early invasive therapy improved long-term outcomes17 which is consistent with the results shown by the TIMACS trial.

Despite all these data, there is still controversy on what the best timing is to perform a CA in patients with NSTEMI.

An important limitation of previous studies is heterogeneity in the definition of early and late CA, and the differences seen in the primary endpoints.4^-14 The lack of uniform criteria makes it difficult to compare the results. The definition of NSTEMI has changed over time. Thus, old clinical trials used a different criterion for the definition of NSTEMI and included different patients from those of current studies. We should try to identify what patients with the highest risk would benefit from an early invasive strategy. In this sense, previous studies did not use risk grading systems to classify patients. However, in our study we calculated the ischemic and bleeding risks of all patients. As our objective was to assess the potential benefit of an early invasive strategy among NSTEMI patients, the GRACE risk score was estimated in the entire study population. However, despite the high ischemic risk of our patients, no significant differences were found between the 2 strategies (early or delayed CA) regarding mortality or adverse events.

Limitations

Our study has several limitations that should be considered when interpreting the results. Although we included a large number of NSTEMI patients with a collection of high quality data, this is an observational, retrospective, single center study with the limitations of this type of study. Besides, the current clinical practice guidelines recommend the PRECISE-DAPT score to assess bleeding risk in this clinical setting. In our study bleeding risk at admission was classified according to CRUSADE score.

CONCLUSIONS

The results of our study show that the early CA strategy did not improve prognosis or reduce mortality in NSTEMI patients. However, larger studies are still needed to clarify which group of patients may benefit from early CA strategies.

CONFLICTS OF INTEREST

None declared.

 

 

REFERENCES