Percutaneous coronary intervention versus coronary artery by-pass grafting in premature coronary artery disease: What is the evidence? -A narrative review

Abstract

Coronary artery disease (CAD) remains one of the leading causes of death globally. In the United States of America, in 2016, 19% of all patients under the age of 65 died of cardiovascular disease despite improvements in primary prevention. The premature clinical onset of symptoms in the young population (<60 years) is much more aggressive than in the older population, and the overall long-term prognosis is poor. CAD appears to have a rapidly progressive form in those under the age of 60 due to genetic predisposition, smoking, and substance abuse, however, the ideal management strategy is still yet to be established. The two primary methods of establishing coronary revascularization are percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG). Despite the increasing prevalence of CAD in the young population, they are consistently underrepresented in major randomized clinical trials of each revascularization strategy. Both CABG and PCI are known to have similar survival rates, but PCI is associated with higher repeat revascularization rate. Many argue this may be due to the progressive nature of CAD combined with the vessel patency time required in a patient under 60 with potentially another 20-30 years of life. There is little in literature regarding the outcomes of these various revascularization strategies in populations under 60 years with CAD. This review summarises the current evidence for each revascularisation strategy in patients under the age of 60 and suggests future avenues of research for this unique age group.

Keywords

coronary artery disease percutaneous coronary intervention coronary artery by-pass grafting revascularisation outcomes young patients future research

Introduction

The two primary methods of establishing coronary revascularization are percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG). Despite the increasing prevalence of CAD in the young population, they are consistently underrepresented in major randomized clinical trials of each revascularization strategy.¹ Around a decade ago, evidence suggested that patients under the age of 60 years may benefit from PCI over CABG, but more recent studies suggest that CABG may be superior.^1,9–11 Recent advancements have propelled the debate between PCI and CABG into new dimensions. Notably, two meta-analyses^12,13 conducted by Formica et al. have provided invaluable insights by comparing 5-years and even 10-years outcomes of these revascularisation strategies. The comprehensive analysis, encompassing 5180 patients, revealed that over the 10-years follow-up, PCI exhibited a higher overall incidence of all-cause mortality (HR, 1.19; 95%CI, 1.04-1.32; p = 0.008). Specifically, PCI demonstrated an increased risk of all-cause mortality within the initial 5 years (HR, 1.2; 95%CI, 1.06-1.53; p = 0.008), while no discernible differences emerged in the subsequent 5–10-year period (HR, 1.03; 95%CI, 0.84-1.26; p = 0.76). Remarkably, the life expectancy of CABG patients surpassed that of PCI patients by a modest yet noteworthy margin of 2.4 months. Patients under the age of 60 were once believed to benefit more from PCI over CABG.^9,11 However, recent studies and meta-analyses suggest a potential superiority of CABG, challenging the previously held consensus1. Both CABG and PCI are known to have similar survival rates, but PCI is associated with higher repeat revascularization rate. Many argue this may be due to the progressive nature of CAD combined with the vessel patency time required in a patient under 60 with potentially another 20-30 years of life.^1,2,14,15 For example, the multi-centre European retrospective study (CRAGS) recruited 1617 patients under the age of 50 years: 13.5% of them showed disease progression, and indications for repeat revascularization included stent thrombosis and restenosis.¹⁴

With recent advances in PCI techniques and with the introduction of drug-eluting stents, PCI is widely used even in multivessel CAD.¹⁶ However, currently, there is little in literature regarding the outcomes of these various revascularization strategies younger populations with CAD.¹⁶ Similarly, most of the data on CABG outcomes report on the risks for elderly patients who undergo coronary revascularization, but research on the impact of age stratification on CABG outcomes is scarce for younger patients with CAD.^1,2,15,17 The definition of ‘young’ patients with CAD is highly heterogeneous in the literature¹⁸; but with average life expectancy rising to early to mid-80s in the West, with many continuing to work well in their 60s,¹⁹ we will consider patients under the age of 60 in our presentation of the literature as ‘young’ patients. Therefore, this narrative review will henceforth summarise the current evidence for each revascularisation strategy in patients under the age of 60.

Acute myocardial infarction in the younger population

It is imperative to understand the aetiologies and presentations of acute myocardial infarction (MI) in those under the age of 60 - to enable a thorough understanding of this disease phenomenon, tailor optimal management and treatments, and help preserve not only the quality but also the quantity of life in this cohort.¹ Despite acute MI predominantly affecting older individuals, a significant proportion of those under 60 years of age - with unique risk profiles, are also impacted by this disease. The main categories that the under 60s with acute MI can get classified into [a] MI related to traditional cardiovascular risk factors like those in older individuals, [b] Recreational drug usage (e.g., methamphetamine and cocaine), [c] MI due to spontaneous coronary artery dissection, [d] coronary vasospasm, and [e] Atheromatous coronary artery disease causing MI but with no critical coronary stenosis.²⁰

Non-ST elevation (NSTEMI) is present in up to two-thirds of patients under 60 presenting with acute MI, with approximately a third presenting with STEMI. (18) Overall, the incidence of STEMI in under 60s has reduced, but the proportion of patients <60 being diagnosed with STEMI is rising.²¹

Generally, the clinical presentation between patients <60 years and >60 years is indistinguishable. However, certain features are noticeable in the former population. Firstly, preceding the MI, angina symptoms are uncommon and only present in approximately one-fourth of patients.²² Secondly, there is no history of chest pain preceding the MI in 69% of patients younger than 45.^23,24 Lastly, there is symptom onset within a week of the MI event.^24,25 Furthermore, coronary angiography depicts less extensive disease in the MI cohort consisting of patients <40 years of age when compared to the older MI cohort.^26,27 Fournier et al. reported that three-vessel disease was not a common occurrence, present in less than 10%, in MI patients <40 years of age.²⁵ Moreover, it was the single-vessel disease entity that was more common in MI patients ≤ 35 years, with the left anterior descending artery frequently affected.²⁸

Percutaneous coronary intervention in the younger population

In 1978, Gruntzig described percutaneous coronary intervention (PCI) as a revascularization technique for patients suffering from a single-vessel disease.²⁹ Subsequently, refinement of PCI has extended its use to treat more complex lesions, which has challenged the “gold standard” role coronary artery bypass grafting (CABG) has played in myocardial revascularization.²⁹

Khera et al. carried out a US study to assess the temporal trends and gender differences in revascularization and in-hospital outcomes of patients <60 years with STEMI.³⁰ Usage of the National database helped narrow down all patients aged 18 to 59 years hospitalised with STEMI. From 2004 to 2011, 1,363,492 younger adults (age <60 years) had acute MI and 632,930 (46.4%) had a STEMI. Additionally, PCI usage for STEMI has increased in young men (63.9% to 84.8%) and women (53.6% to 77.7%). Furthermore, the authors concluded that the use of PCI for STEMI and in-hospital mortality has increased, whereas the length of hospital stay has decreased over the years – for both genders.³⁰

The authors of the CRAGS study (coronary artery disease in young adults), a multi-centre European retrospective registry, enrolled 1617 patients (age ≤50 years).¹⁴ The majority of patients in this study were smokers. They also were prescribed adequate secondary prevention, for instance, statins and aspirin. At 5 years follow up, the following data arose - survival was 97.8%, no occurrence of major adverse cardiac and cerebrovascular events was 74.1%, no-repeat revascularisation was 77.8%, and no myocardial infarction was 89.9%. However, 13.5% displayed disease progression and had subsequent repeat revascularisation. Some of the other indications for repeat revascularisation were stent thrombosis (2.1%) and restenosis (7.1%).¹⁴ The data from this study suggests that mortality was low after PCI in patients ≤50 years old, and apart from repeat revascularisations, the occurrence of severe events was uncommon. However, the retrospective nature of the study is a significant limitation.

Konishi et al.’s retrospective study evaluated the long-term prognosis of PCI in adults ≤40 years³¹ Specifically, data regarding young Japanese adults, n = 69 – aged ≤40 years and 96% of these were men, was analysed. Current smokers made up 30% of the cohort, with a body mass index (BMI) of 26.7 ± 5.0 kg/m². Furthermore, the prevalence of hypertension and diabetes was 48% and 33%, respectively. The overall death rate was 5.8% at a median follow up (9.8 years). The authors from this study concluded that long term prognosis is acceptable, and that current smoking emerged as a rather significant independent predictor of death.³¹ The sample size pertaining to young adults was small, and the study was at a single centre which may have introduced bias.

The data from the PCI registry of the Euro Heart Survey illustrates that post-adjustment of confounding variables, the age group with the lowest mortality is the 40–50 age bracket.^32,33 Surprisingly, this data also depicts that patient under 40 years have a slightly increased risk.³² There have been speculations about the potential factors behind these findings with no specific reason found.

Patient age plays a role in the outcomes of PCI. However, Epps et al. highlighted the impact of both gender and age on the outcomes of PCI.³⁴ The authors used the National Heart, Lung and Blood Institute Dynamic Registry to evaluate associations between gender and age on cardiovascular-related outcomes in 10,963 patients (n = 3797 were women, n = 394 were <50 years) who had undergone PCI and had a 5 year follow up. This study showed that despite young women having less severe angiographic coronary artery disease, they possessed an increased risk of the target vessel and target lesion failure.³⁴

To conclude, large scale thorough research is needed to assess the age and gender-associated risk in patients specifically <60 years who have had PCI. The implications on the decades of future life expectancy and quality of life are significant and warrant further detailed research in this cohort of patients.

Coronary artery bypass grafting choice in <60 years old (single left internal thoracic artery or bilateral internal thoracic arteries) - is there a need for further evidence?

Coronary artery bypass grafting (CABG) is a surgical procedure where an affected coronary artery is bypassed using artery or vein conduits³⁵ harvested from another site. The single left internal thoracic artery (SITA) to the left anterior descending artery (LAD) has been the standard choice of conduit over saphenous vein graft (SVG).³⁶ This is because SITA has a 45% greater rate of patency at 10 years which resulted in a better survival rate.³⁷ However, there is emerging evidence supporting the use of bilateral internal thoracic arteries (BITA) over SITA to provide survival benefit.³⁸ A recent meta-analysis of propensity score-matched observational studies showed a significant long-term survival for BITA compared to the SITA group.³⁹ It is important to determine if BITA is better than SITA for <60 years old as they, who have a longer life expectancy, will most likely benefit from this.

Patients who undergo BITA tend to be younger than SITA.^40,41 However, it is important to analyse if the trend is similar when the patient group is adjusted to <60 years old. In 2001, it was observed that the age of BITA patients was significantly (p = .002) younger compared to SITA, in a group of young patients (BITA = 53.7 years, SITA = 56 years).⁴² The same pattern is still seen up to 2020.^43,44 This might be explained by the benefits of BITA over SITA that are only evident after several years. In fact, it takes at least 7 years after the operation to attain lower rates of mortality in BITA over SITA.⁴⁵ There was no difference in the number of deaths within 30 days between SITA and BITA (0.5% vs 0.5%) in those <60 years old.⁴³ In addition, there were significantly more angina-free patients in BITA compared to SITA (84% vs 72.7%, p = .006) However, this is contradicting to the data provided by Berreklouw et al where at 13 years follow up, the overall survival rates were not significantly different between BITA and SITA (76.2% vs 78.3%) patients with a mean age of 53.7 and 56 years old, respectively.⁴² Patients <60 can benefit from a greater survival advantage in BITA but the length of time it takes for this effect to be evident is not apparent. More evidence is needed to determine the number of years it takes for BITA to show benefits in those <60 years old.

The evidence from a qualitative study using the Likert scale and WHOQOL-BREF questionnaires by Zebalski et al indicated that quality of life is improved subjectively and objectively when BITA is compared to SITA at long-term follow up (3568 days). The patients who had BITA and SITA were 57.5 and 59.4 years old, accordingly. Moreover, it was found that patients’ age is weakly and negatively correlated with quality of life. (r = −0.14, p = .01)⁴⁴ This is consistent with the data provided by Gaudino et al where younger patients with BITA had significantly lower major adverse events (MAE) when the population sample from Arterial Revascularisation Trial (ART) was restricted to 50–70 years old.⁴⁶ However, this effect disappears when the population isn’t restricted to 50–70 years old.⁴⁶ The possible explanation for this is the shorter life expectancy in the older population which can hold back the benefit of BITA over SITA.⁴⁵ However, in a retrospective analysis of 660 subjects with triple-vessel coronary artery disease,⁴⁷ comparing the outcomes of those who received BIMA in addition to either RA (n = 206) or SV (n = 454) grafting. The results showed no significant difference in in-hospital mortality between the BIMA + RA and BIMA + SV groups. Over a median follow-up of 9.2 years, long-term survival rates at 5, 10, and 15 years demonstrated no statistically significant difference between the two group. The authors concluded that the use of RA as a third arterial conduit with BIMA did not confer a long-term survival benefit. Therefore the team conducted a meta-analysis focusing on the comparison of long-term outcomes between coronary artery bypass grafting using BIMA and RA (BITA + RA) versus BIMA and SV (BITA + SV).⁴⁸ The meta-analysis included six propensity score-matched studies involving 2500 patients. The results indicated that the use of BITA + RA was not associated with higher early mortality compared to BITA + SV. However, the pooled analysis of long-term survival favoured BITA + RA treatment, with a significant difference between the two groups at 5, 10, and 15 years. The findings suggested that BITA + RA usage in CABG is not associated with higher operative risk and is linked to superior long-term overall survival. The limited literature appears to show that BITA alone may improve long-term outcomes in those <60 years old. However, further evidence is needed to determine the association of age and outcome of BITA versus SITA in a population from ART restricted to <60 years old.

Does the number of diseased vessels matter in the outcome of percutaneous coronary intervention?

In practice, it is imperative to acknowledge the differences in clinical profile and the outcomes following PCI in <60 years old, between single vessel disease (SVD) and multiple vessel disease (MVD). This is because atherosclerotic plaques in multiple vessels are seen to be associated with worse outcomes in many studies.^49,50

Thrombolysis in myocardial infarction (TIMI) is a useful predictor for the outcome as low post-interventional grade (≤2) is strongly associated with adverse outcomes during and after hospitalisation following PCI.⁵¹ In a study that used subsequent TIMI flow grades to evaluate MVD and SVD, Majeed et al. revealed that there is no association between post-procedure TIMI flow grade and the number of vessels in patients with an average age of 56.3 years. PCI can be used regardless of the number of diseased vessels.⁵² There were similar findings in another study where the number of diseased vessels and TIMI flow grade 3 was observed in MVD versus SVD as 98% versus 96.5% (p = NS).⁵³ However, the population in both the studies is dominated by men, 81%⁵² and 87.7%,⁵³ respectively. This may create potential bias as a result. Hence, further evidence is needed for people <60 years old where gender bias is eliminated.

It has been shown in many studies that MVD patients have a higher rate of mortality compared to SVD.^54,55 It is therefore important to observe if this is still valid when the age of the population is restricted to <60 years old. The data from a retrospective cohort study of <46 years old conducted by Muhammad et al revealed that the difference in post-procedure in-hospital outcomes after PCI is insignificant between MVD and SVD. Although insignificant, MVD patients do tend to have worse outcomes compared to SVD. For example, the in-hospital mortality is higher in MVD versus SVD (0.9% vs 0.0%).⁵³ In contrast, this difference in in-hospital mortality is highlighted as significant (11.48% vs 3.03%, p = .015) in another study by Batra et al with patients of a mean age of 54.77 years old.⁵⁶ However, the sample size in Muhammad et al (n = 571) is double the number in Batra et al (n = 282) which may impact the weighting of Batra’s result.^53,56 This is important as in <60 years old, the proportion of patients that have MVD ranges from 40.1% to 64.89% in different studies with various sample sizes.^52,53,56 Further studies should contain larger samples to create a more representative value for the population <60 years old.

To conclude, there are conflicting evidence regarding the association between the number of diseased vessels and adverse outcomes post-PCI for <60 years old.^51,53,56 The paucity of evidence with samples below 60 years old makes it unclear whether or not the association is valid.

Comparison of clinical outcomes

In clinical practice, PCI is mainly performed in the under 60s as the emergency treatment for acute MI, or at the other end of the spectrum in stable patients with single-vessel CAD. CABG on the other hand is more frequently undertaken for multivessel disease and associated co-morbidities.^1,3 Therefore, the literature for direct comparisons of PCI and CABG in this patient group (<60 years) is limited (summarised in Table 1). In patients under the age of 60, regardless of degree of CAD disease, the weight of the literature suggests that both PCI and CABG have good long-term outcomes for traditional ‘hard endpoints’ (all-cause mortality, MI and stroke).^{1,15,16,57–63} These findings fall in line with the wealth of evidence in patients over the age of 60.^64–66 The pooled analysis by Flather et al. appears to suggest that PCI is superior for long-term mortality when compared to CABG, which is in direct conflict to a more recent study by Robich et al. However, Flather et al. results were not adjusted for the type of ACS at presentation, which may explain their conflicting findings, as Biancari and colleagues suggest that despite no difference in long-term mortality, there may be an improved 30-days mortality with PCI following STEMI.^1,15,59 Conversely, the improvements in long-term survival of patients undergoing CABG shown by Robich et al. may be in part explained using arterial conduit for revascularisation,⁶⁷ as 11.1% of their cohort had multi-arterial grafting. More work needs to be done to determine the effects of multi-arterial grafting in long-term outcomes and the value of PCI over CABG in STEMI in patients under the age of 60 years.

Table 1.

Summary of outcomes of CABG versus PCI in younger patients.

Study	Design	Age	n	Disease	Follow-Up	Primary Endpoint (s)	Secondary Endpoint (s)	Results	Conclusions
Buszman et al. 2009	Retrospective single centre 10 Year follow-up of SOS trial patients	PCI = mean 54.7 +/− 8.8	CABG = 50 PCI = 50	MVD	10 years	LVEF	MACCE, CCS, survival, and RR	Rr: PCI vs CABG = 42% vs 18% (p < .05) MACCE: 36 vs 28 (p < .05) survival, CCS, LVEF = NS	PCI or CABG have very similar 10-years outcomes with respect to mortality, CCS, LVEF, and MACCE other than RR in MVD
Buszman et al. 2009		CABG = mean 52.7 +/− 9.1 years	CABG = 50 PCI = 50	MVD	10 years	LVEF	MACCE, CCS, survival, and RR
Hlatky et al. 2009	Pooled analysis of 10 randomised trials	<55 years	CABG = 3889 PCI = 3923	MVD	Median = 5.9 years (IQR 5.0-10.0)	All-cause mortality	Death or MI within 90 days	5-Year mortality <55 years: CABG vs PCI = 5.5% vs 5.0% HR = 1.25 (p = .002)	Long-term mortality is similar after CABG and PCI in MVD, choice of treatment should depend on patient preferences for other outcomes
Flather et al. 2012	Pooled analysis of 10 randomised trials	≤56.2 years	CABG = 2586 PCI = 2621	MVD	Median = 5.9 years	All-cause mortality	Death or MI, death, MI or RR	All-cause mortality: CABG vs PCI = HR = 1.23 (0.97-1.60 p < .01)	All-cause mortality was lower among younger patients assigned to PCI than among those assigned to CABG
								Death or MI: HR = 1.22 (1.00-1.47 p < .01)
								Death, MI or RR: HR = 0.23 (0.20-0.28 p < .01)
Biancari et al. 2014	Retrospective analysis of 15 European institutions	≤50 years	CABG = 592 PCI = 1617	Diagnosis of stable angina, unstable angina, NSTEMI, STEMI	30 days, 1-year, 3-year, 5-year	FF MACCE	All-cause mortality, freedom from stroke, RR, and MI	5-Year FF MACCE: CABG vs PCI = 85.0% vs 73.9% (p < .0001)	CABG is associated with greater freedom from MI and RR. In STEMI, PCI is associated with a lower 30-day mortality than CABG
								5-Year FF RR: 92.5% vs 77.6% (p < .0001)
								5-Year FF MI: 96.6% vs 89.9% (p < .0001)
								STEMI: 5-Year Survival = 88.8%vs97.5% (p = .001) and 30-day Mortality = 6.0% vs 1.5% (p = .017)
Li et al. 2017	Single centre retrospective analysis	≤45 years	CABG = 406 PCI = 406	DM and CAD: Stable angina, unstable angina, silent ischaemia, STEMI, NSTEMI	10 years	10-Year survival	FF MACCE, FF stroke, FF RR, FF MI	Survival: CABG vs PCI = 1-year = 99.8% vs 98.7% (p = .0062) 5-year s= 98.6% vs 96.1% (p = .0024) 10-years = 97.3% vs 94.5% (p = .0072)	DM patients aged ≤45 years, survival, FF MI and RR for CABG were superior to those of PCI
								FF stroke: 1-year = 99.6% vs 99.0% (p = .0164) 5-year s= 98.1% vs 98.3% (p = .0666) 10-year s= 94.2 vs 97.5% (p = .0059)
								FF RR: 1-year = 100% vs 98.9% (p = .01) 5-year s= 98.6% vs 96.5% (p = .0079) 10-years = 98.1% vs 95.8% (p = .0113)
								FF MI: 1-year = 99.8% vs 97.7% (p > .0001) 5-year s= 98.1% vs 93.5% (p < .0001) 10-year s= 96.1% vs 91.8% (p = .0005)
								FF MACE:1-year = 99.0% vs 96.9% (p < .0001) 5-year s= 95.6% vs 89.6% (p < .0001) 10-years = 93.2% vs 86.3% (p < .0001)
Leviner et al. 2019	Single centre retrospective analysis	<40 years	CABG = 93 PCI = 90	CAD: Stable angina, unstable angina or MI	Median = 6.5 years	MACCE	All-cause mortality, MI, CVA, and RR	MACCE: CABG vs PCI: HR = 0.305 (0.146-0.637 p < .01)	Patients <40 years treated with CABG showed a reduction in the risk for non-fatal cardiac events. Mortality was similar with CABG and PCI
								Rr: HR = 0.205 (0.090-0.464 p < .01)
								All-cause mortality: HR = 1.168 (0.256-5.338 p = .84)
								MI: HR = 0.236 (0.047-1.638 p = .24)
Park et al. 2019	Retrospective analysis of the IRIS-MAIN registry	<60 years	CABG = 391 PCI = 914	LMD	Median = 6.3 years (IQR 4.0-9.4)	Composite all-cause death, MI or stroke at 5-year	All-cause mortality, RR, MACCE	Primary endpoint and all-cause mortality: PCI vs CABG: NS	There is no significant difference between CABG and PCI in LMD. Differences in MACCE are driven by PCI>CABG RR
								Rr: HR = 3.62 (2.11-6.23 p < .001)
								MACCE: HR = 1.81; (1.22-2.68 p = .003)
Chen et al. 2020	Single centre retrospective analysis	≤45 years	CABG = 81 PCI = 132	LMD and/or MVD	38 Months (IQR 36-41 Months)	MACCE	All-cause mortality, MI, stroke, and RR	MACCE: CABG vs PCI: HR = 3.263 (1.379-7.722 p = .007)	Patients ≤45 years with LMD or 3VD, PCI showed a higher incidence of MACCE, which was mainly driven by RR. However, this did not translate into hard endpoints
								Rr: HR = 6.968 (2.036-23.842 p = .002)
								All-cause mortality, MI and Stroke = NS
Robich et al. 2020	Retrospective Analysis of 7 Medical Centres	<60 years	CABG= 1945 PCI= 2938	≥70% Stenosis in ≥1 MCA	Mean= 6 years	All-Cause Mortality	Stroke, RR, 30-Day Mortality	10-Year Survival: CABG vs PCI: HR= 0.71 (0.57-0.88 P= 0.002)	Patients<60 years with 2VD, including LAD or 3VD, CABG was associated with greater long-term Survival and decreased risk of RR
								Stroke: 1.3% vs 0.07% (P <0.001)
								10-Year RR: HR= 0.34 (0.28-0.40 P<0.001)
Shafi et al. 2020	Retrospective Analysis in	≤50 years	CABG= 100 PCI= 100	CAD	5 and 12 years	MACCE	MI and RR	MACCE: CABG vs PCI: 5-Year= 12 vs 34 (P <0.01) 12-Year= 40 vs 51 (P= 0.07)	MACCE was lower in CABG at both 5 and 12 years primarily as a consequence of patients with 3VD undergoing PCI having more MI and RR
								MI: 5-Year = 1% vs 9% (p = .02)
								Rr: 5-year s= 7% vs 31% (p < .01) 12-Year = 20.4% vs 41.1% (p < .01)

PCI = percutaneous coronary intervention CABG = coronary artery bypass graft HR = hazard ratio 95% confidence intervals MVD = multivessel disease LVEF = left ventricular ejection fraction MACCE = major adverse cardiac and cerebrovascular events CCS = canadian cardiology society class RR = repeat revascularisation NS = not significant (p > .05) IQR = inter quartile range MI = myocardial infarction FF = freedom from NSTEMI = Non-ST myocardial infarction STEMI = ST-elevation myocardial infarction 1, 2, 3VD = 1, 2, and 3 vessel disease HF = heart failure DM = diabetes mellitus CVA = cerebrovascular accident LMD = left main disease MCA = main coronary artery ACS = acute coronary syndrome.

Despite similar outcomes in hard endpoints, the literature suggests that in patients <60 years with CAD, CABG is associated with a clear benefit in avoiding repeat revascularisation (Table 1).^{1,15,16,57–63} This reflects the findings seen in the overall CAD population.^64,66 This benefit may be explained by the progressive nature of atherosclerosis and CAD, which is combated using venous grafting in CABG, whereas PCI which treats individual arterial stenoses.³ This reasoning may also explain the more pronounced benefit of CABG in CAD complicated by multi-vessel involvement^1,16,63 and diabetes mellitus.⁶⁰ Furthermore, patients which premature CAD (<60 years) are more likely to have genetic factors predisposing them to CAD less amenable to secondary prevention and are known to be less compliant with medical management, therefore more research is required to determine the preventative effect of CABG in this age group.^61,68

Risk stratification for revascularisation

Risk stratification based on baseline patient characteristics is vital to determine the most appropriate revascularisation strategy in CAD, as demonstrated by the SYNTAX trial.⁶⁴ However, the data in patients <60 years is particularly scarce (Summarised in Table 2). There appears to be a clear benefit from CABG in diabetic patients in long-term mortality and major adverse cardiac and cerebrovascular events (MACCE), including repeat revascularisation,^{1,15,58,69,70} as well as in multi-vessel disease.^15,16 These findings are in line with the evidence in older patients^9,71,72 and current revascularisation guidelines which recommend CABG in these patients.⁷³ CABG also appears to have a benefit in patients who have had a prior MI⁶³ and worsening ejection fraction.¹⁶ Smoking has been shown in two studies to be a predictor of adverse outcomes following PCI,^31,74 this has yet to be explored for CABG in patients under 60 years. Traditional CAD risk factors such as sex, hypertension, obesity, and heart failure do not appear to influence outcomes preferentially for either revascularisation approach.^{58,62,63,69,75} On review of the literature, more work needs to be done assess the factors influencing outcomes from revascularisation in patients <60 years with CAD, as risk stratification has been shown to be crucial in maximising outcomes in older patients.^64,65,73

Table 2.

Summary of factors effecting outcomes in <60 years.

Study	Design	Age	n	Disease	Follow-up	Co-morbidities	Results	Conclusions
Hlatky et al. 2009	Pooled analysis of 10 randomised trials	<55 years	CABG = 3889 PCI = 3923	MVD	Median = 5.9 years (IQR 5.0-10.0)	DM, sex, smoking, HTN, hypercholesterolaemia, PVD, angina stability, previous MI, HF, LV function, 3VD, proximal LAD, balloon vs bare-metal stents	DM 5-year mortality: CABG vs PCI No DM = 7.6% vs 8.1% DM = 12.3% vs 20.0% (p = .014) sex, smoking, HTN, hyperlipidaemia, PVD, angina stability, previous MI, HF, LV function, 3VD, proximal LAD, balloon vs bare-metal stents = NS	The interaction of DM with treatment remained after adjustment for age, sex, smoking, HTN, history of MI, HF, and 3VD
Biancari et al. 2014	Retrospective analysis of 15 European institutions	≤50 years	CABG = 592 PCI = 1617	Diagnosis of stable angina, unstable angina, NSTEMI, STEMI	30 days, 1-year, 3-year, 5-year	DM (+MVD)	DM 5-year survival: PCI vs CABG = NS	No significant survival difference. CABG was associated with lower risk of MACCE, MI,and RR. This was more pronounced in the patients with 2-to-3-VD and SCAD
							DM 5-year FF MACCE: 58.0% vs 75.9% (p < .0001)
							DM 5-year FF MI: 83.6% vs 93.3% (p = .004)
							DM 5-year FF stroke: 96.5% vs 100% (p = .035)
							DM 5-year FF RR: 61.9% vs 88.3% (p < .0001)
Konishi et al. 2014	Retrospective single centre analysis	≤40 years	PCI = 69	ACS	Median 9.8 years (IQR 3.9-18.8 years)	Smoking	Smoking all-cause death and ACS: HR: 4.46 (1.08-19.1 p = .04)	Smoking was the only long-term predictor of outcome in young patients undergoing PCI
Poddar et al. 2016	Analysis of Cleveland Clinic PCI database	≤45 years	PCI = 1640	CAD	13.15 years	DM, obesity	DM long-term mortality: 19.4% vs 9.3% (p < .001) obesity: NS	Young DM patients have worse long-term outcomes after PCI
Park et al. 2019	Retrospective analysis of the IRIS-MAIN registry	<60 years	CABG = 391 PCI = 914	LMD	Median = 6.3 years (IQR 4.0-9.4)	Sex	Composite death, MI or stroke	There is no significant interaction with sex and choice of revascularization in <60 years
Park et al. 2019	Retrospective analysis of the IRIS-MAIN registry	<60 years	CABG = 391 PCI = 914	LMD	Median = 6.3 years (IQR 4.0-9.4)	Sex	All-cause mortality, RR, MACCE interaction with Sex = NS
Wang et al. 2019	Retrospective single centre analysis	≤45 years	PCI = 203	ACS	1 year	DBP, HbA1c, TnT	HbA1c RR: HR: 1.835 (1.358-2.479 p = 0)	HbA1C was an independent predictor for the incidence of RR Post-PCI
Chen et al. 2020	Single centre retrospective analysis	≤45 years	CABG = 81 PCI = 132	LMD and/or MVD	38 Months (IQR 36-41 Months)	Sex, HTN, DM, prior MI, prior HF, LMD, Gensini score	Prior MI MACCE: PCI vs CABG HR: 0.652 (0.125-3.397 p = .0031)	There were no significant interactions between any treatment effects of PCI versus CABG in the rate of MACCE except for the prior MI
Chen et al. 2020	Single centre retrospective analysis	≤45 years	CABG = 81 PCI = 132	LMD and/or MVD	38 Months (IQR 36-41 Months)	Sex, HTN, DM, prior MI, prior HF, LMD, Gensini score	Sex, HTN, DM, prior HF, LMD, Gensini = NS
Shafi et al. 2020	Retrospective analysis in barts health NHS trust	≤50 years	CABG = 100 PCI = 100	CAD = reduction >50% of the vessel lumen diameter, 1-3VD +/− LMS stenosis	5 and 12 years	1VD, 2VD, 3VD, EF, DM	3VD 5-year MACCE: PCI vs CABG 8 (n = 22) vs 10 (n = 79) (p = .02)	CABG should remain the preferred method of revascularization in young patients with 3VD, DM, and those with worsening EF
							3VD 5-year RR: 36.4% vs 7.6% (p < .01) 1VD and 2VD RR = NS
							3VD 12-year MACCE: 19 (n = 21) vs 31 (n = 78) (p < .01)
							3VD 12-year MI: 47.6% vs 19.2% (p < .01) 3VD 12-year RR: 66.7% vs 20.5% (p < .01) DM 12-year RR: 50% vs 11.8% (p = .022) 12-year survival moderate EF CABG>PCI HR = 0.02 (0.01-0.12 p < .1)
							12-Year survival Poor EF: CABG> PCI HR = 0.07 (0.01-0.37 p < .01)

PCI = percutaneous coronary intervention CABG = coronary artery bypass graft HR = hazard ratio 95% confidence intervals MVD = multivessel disease LVEF = left ventricular ejection fraction MACCE = major adverse cardiac and cerebrovascular events RR = repeat revascularisation NS = not significant (p > .05) IQR = inter quartile range MI = myocardial infarction FF = freedom from NSTEMI = non-ST myocardial infarction STEMI = ST-elevation myocardial infarction 1, 2, 3VD = 1, 2, and 3 vessel disease HF = heart failure DM = diabetes mellitus LMD = left main disease HTN = hypertension PVD = peripheral vascular disease LAD = left artery disease NYHA = new york heart association class ACS = acute coronary syndrome.

Future research

Upon review, the evidence for the optimum revascularisation strategy in patients under 60 years is limited in both quantity and quality. Much of the data comes from retrospective analyses of single centres or registries. Although the data appears to replicate what is seen in older patients,^64–66 randomised controlled trials of CABG and PCI in this population would provide a better reference for comparing their effectiveness due to their increased statistical power.⁵⁸ Higher quality research in this population is of particular importance as death rates from CAD appear to be falling more slowly in younger age groups,⁷⁶ and the prevalence of risk factors: smoking, diabetes, reduced exercise, and subsequent obesity have increased threefold in this population in the UK in the previous decades.⁷⁶ Furthermore, the progressive nature of atherosclerosis means that determining the optimal revascularisation strategy for these patients, who are likely to have more aggressive genetic and lifestyle risk factors, needs to balance short-term goals of returning to work and family, as well as long-term reduction of future adverse events.^1,63

The main differentiating factor between the approaches appears to be the increased rate of repeat revascularisation with PCI when compared to CABG (Table 1), with Biancari and colleagues reporting that repeat revascularisation was the driver of over half of their reported MACCE.¹⁵ Future research should therefore endeavour to compare the revascularisation approaches by optimising the procedural technique and risk stratification of patients <60 years, to reduce the rate of repeat revascularisation.^61,65 In CABG, more work needs to be done to establish the short and long-term benefits of: on versus off-pump approaches,⁷⁷ the conduit used to re-establish perfusion,^1,16 and the advantage of total arterial revascularisation.⁷⁸ In PCI, more work needs to be done to establish the benefit of pre-procedure risk stratification to potential reduce the rate of revascularisation. Fractional flow reserve (FFR) in pre- and post-procedure assessment was demonstrated in the FAME trial to reduce the rate of MACCE by providing more detail in repeat revascularisation decisions,⁷⁹ which is particularly pertinent with Chen and colleagues reporting that many young PCI patients receive repeat revascularisation that is largely angiographically driven, rather than clinically supported.⁶³

Patients undergoing revascularisation before the age of 60, with potentially many years ahead of them, need not only receive the right intervention, but also need to be managed with the optimum adjuvant medical therapy to minimise their risk of repeat revascularisation and future adverse events, as they may have more aggressive risk factors.^15,60,61 Future research must therefore also establish the adjuvant medical regimens required for each intervention and tackle the poorer drug compliance seen in this unique patient population.^17,61,68 Furthermore, more research is required to establish concrete treatment pathways in patients under 60 years requiring revascularisation, based on SYNTAX,^1,65,75 extent of CAD,¹ genetics and family history,^1,61 and traditional CVD risk factors^16,57,62 to compare with well-supported guidelines in older patients over the age of 60.⁷³

Conclusion

The prevalence of CAD requiring revascularisation in the under 60s is on the rise and more aggressive than in the older patients. The two most widely used treatment strategies for coronary artery revascularization are PCI and CABG, but which treatment modality is superior in this unique population (<60-year-olds) is a complex and highly debated question to date. Although many RCTs have investigated the outcomes of CABG and PCI, the younger population remain underrepresented. With seminal trials, such as SYNTAX, BEST, and FREEDOM suggesting the superiority of CABG in particularly repeat revascularization in older patients, trials on a similar scale are required in younger patients with different treatment priorities. Further research is required to establish the most appropriate revascularisation strategy and adjuvant medical therapy in this unique patient group to compare with well-established guidelines in older patients.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Christopher J Goulden

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