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 Table of Contents  
RECENT LANDMARK TRIALS
Year : 2018  |  Volume : 7  |  Issue : 1  |  Page : 34-37

Recent Landmark Trials: From Primordial Prevention to Myocardial Revascularization- A Lot to Ponder!


Department of Cardiology, Medanta- The Medicity, Gurgaon, Haryana, India

Date of Web Publication11-Jan-2018

Correspondence Address:
Dr. Manish Bansal
3rd Floor OPD, Medanta - The Medicity, Gurgaon - 122 001, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCPC.JCPC_51_17

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How to cite this article:
Bansal M, Kasliwal RR. Recent Landmark Trials: From Primordial Prevention to Myocardial Revascularization- A Lot to Ponder!. J Clin Prev Cardiol 2018;7:34-7

How to cite this URL:
Bansal M, Kasliwal RR. Recent Landmark Trials: From Primordial Prevention to Myocardial Revascularization- A Lot to Ponder!. J Clin Prev Cardiol [serial online] 2018 [cited 2020 Nov 26];7:34-7. Available from: https://www.jcpconline.org/text.asp?2018/7/1/34/222929




  Normal Low-Density Lipoprotein-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors Top


Fernández-Friera L, Fuster V, López-Melgar B, Oliva B, García-Ruiz JM, Mendiguren J, et al. J Am Coll Cardiol 2017;70:2979-91.


  Trial Summary Top


Background: Although individuals without major cardiovascular risk factors (CVRFs) are at low risk of having adverse CV events, it is not known at what level of these CVRFs, atherosclerosis actually starts to occur.

Methods: This was a subgroup analysis of the Progression of Early Subclinical Atherosclerosis (PESA) study, which recruited 4184 middle-aged adults, free of CV disease, to evaluate early progression of atherosclerosis. Of the total PESA cohort, 1779 participants (mean age: 45.0 ± 4.1 years, 50.3 women) without conventional CVRFs were included in this analysis. The absence of CVRFs was defined as no treatment for any of the CVRFs, blood pressure (BP) <140/90 mmHg, total cholesterol <240 mg/dl, low-density lipoprotein cholesterol (LDL-C) <160 mg/dl, high-density lipoprotein cholesterol >40 mg/dl, fasting glucose <126 mg/dl, and no smoking. In addition, a further subgroup of 740 individuals with optimum level of these CVRFs was also analyzed separately. The optimum levels were defined as BP <120/80 mmHg, total cholesterol <200 mg/dl, fasting glucose <100 mg/dl, and glycosylated hemoglobin <5.7%. The presence of subclinical atherosclerosis was assessed at 6 different vascular sites in the form of plaques in bilateral carotids, in bilateral iliofemoral arteries, and in infrarenal abdominal aorta (all evaluated using ultrasound) and calcium in coronary arteries (assessed using computed tomography).

Results: It was found that despite the absence of conventional CVRFs, 49.7% of all the study participants had at least some evidence of subclinical atherosclerosis, with nearly half of them (26.9% of the entire cohorts) having involvement of at least 2 vascular sites. Even among those with optimum level of CVRFs, 37.8% had evidence of subclinical atherosclerosis. Male sex, age, and LDL-C were independently associated with the atherosclerosis presence and extent, in both the CVRF-free and CVRF-optimal groups. Every 10 mg/dl increase in LDL-C was associated with an odds ratio of 1.14–1.18 (P < 0.01) for the different measures of subclinical atherosclerosis. In the CVRF-free group, glycosylated hemoglobin was also an independent predictor of atherosclerosis presence and extent.

Conclusions: Subclinical atherosclerosis is common even in individuals considered to be free of conventional CVRFs and even in those having optimum levels of these CVRFs.


  Perspective Top


Lipid-lowering studies in secondary prevention setting have consistently demonstrated that despite a significant relative risk reduction in the aggressively treated arm, the absolute risk of CV events remains considerably high in these individuals. This high residual risk is attributed to the high burden of atherosclerosis that has already set in by the time intervention is undertaken. These observations have drawn increasing attention toward the need to prevent atherosclerosis from allowing to develop at all.

Autopsy studies have shown that the process of atherogenesis starts to occur during the adolescence/early adulthood itself. However, even at that stage, the burden of atherosclerosis seems to correlate with the risk factor burden. Accordingly, maintaining low levels of CVRFs from early adulthood itself is crucial for true primary prevention of atherosclerotic CV disease (ASCVD). Indeed, Mendelian studies have demonstrated that mutations resulting in only marginally low LDL-C levels throughout one's lifetime are associated with drastic reductions in the risk of CV events, which is substantially greater than what can be achieved through statins or any other intervention at a later stage in life. The findings from the PESA subgroup published in this article further extend these observations. These findings strongly support the need for early and effective control of various CVRFs, in particular LDL-C, to levels below the currently accepted thresholds, to achieve effective primordial and primary prevention of ASCVD. This study also demonstrates utility of atherosclerosis imaging in monitoring optimum vascular health and guiding strategies aimed at prevention of ASCVD.


  Surgical Versus Percutaneous Coronary Revascularization in Patients With Diabetes and Acute Coronary Syndromes Top


Ramanathan K, Abel JG, Park JE, Fung A, Mathew V, Taylor CM, et al. J Am Coll Cardiol 2017;70:2995-3006.


  Trial Summary Top


Background: Several different studies have shown that in patients with diabetes with multivessel coronary artery disease (MV-CAD), coronary artery bypass grafting (CABG) is associated with better clinical outcomes as compared to percutaneous coronary intervention (PCI). However, these evidences have been generated from randomized controlled trials and their applicability to real-life clinical practice is not well established.

Methods: This was an observational study, set in British Columbia, Canada. All diabetic patients who underwent coronary revascularization between 2007 and 2014 (n = 4661, mean age approximately 65 years, 27% women) were included in the analysis. Patients with following characteristics were excluded – single vessel disease or left main CAD, two or more chronic total occlusions, ST-elevation myocardial infarction (MI) within the past 72 h, Class III-IV congestive heart failure, prior CABG or PCI within the past 6 months, prior valve surgery, and stroke within the past 6 months. The rates of major adverse CV events (major adverse cardiovascular event [MACE], defined as a composite of all-cause death, nonfatal MI, and nonfatal stroke) were recorded over short term (30-day postrevascularization) and long term (31-day–5-year, median follow-up 3.3 years). The MACE rates were compared between PCI and CABG groups and also stratified according to clinical presentation (stable CAD or acute coronary syndrome [ACS]).

Results: A total of 4819 procedures (2888 PCI, 1931 CABG) were performed in 4661 participants during the study period. Patients who underwent CABG were significantly younger, less likely to be female, less likely to present with ACS (54.4% vs. 68.1%), and had lower prevalence of peripheral arterial disease, pulmonary disease, and left ventricular dysfunction. However, they had more triple-vessel disease (64.3% vs. 28.2%) and more proximal left anterior descending (LAD) coronary artery involvement (45.0% vs. 23.6%) as compared to those undergoing PCI. Nearly two-thirds (63%) of the patients had presented with ACS. They had more left ventricular dysfunction, but no difference with respect to triple-vessel disease or LAD artery involvement. Among ACS patients, 65.2% underwent PCI and 34.8% underwent CABG. At 30-day postrevascularization, MACE rates were significantly lower with CABG in the ACS patients, but no difference was seen in the stable CAD group [Figure 1]. However, at long-term follow-up, CABG was found to have better outcomes in both ACS and stable CAD groups. These findings did not change when the analysis was restricted to the patients receiving only drug-eluting stents (DES) in the PCI group.
Figure 1: Major adverse cardiovascular event rates according to the mode of revascularization. ACS=Acute coronary syndrome, CABG=Coronary artery bypass grafting, CAD=Coronary artery disease, MACE=Major adverse cardiovascular event, PCI=Percutaneous coronary intervention

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Conclusions: In diabetic patients with MV-CAD, compared with PCI, CABG was associated with a lower rate of MACE in the ACS group over short term and in both ACS and stable CAD groups over long term.


  Perspective Top


The preferred modality for myocardial revascularization in diabetics with MV-CAD continues to remain a subject of controversy. The recently published Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-vessel Disease (FREEDOM) trial (N Engl J Med 2012;367:2375-84) showed that in patients with stable CAD at least, CABG was superior to PCI. However, the applicability of these findings outside the setting of a randomized controlled trial remained speculative. Moreover, the FREEDOM study had excluded patients presenting with ACS within the past 72 h.

The present observational study was conducted to address these unanswered questions. This study not only seemed to confirm superiority of CABG over PCI in stable CAD patients but also demonstrated the same in the ACS setting. However, the study was unable to address the influence of various confounders on the clinical outcomes in the PCI and CABG groups. Another important limitation of this study was that data regarding the use of second-generation DES was not available. The authors attempted to draw indirect inferences by analyzing the outcomes according to the year in which the procedure was performed. No interaction was found with respect to the procedure year indicating the possible lack of any impact of the use of second-generation DES on the overall study findings.

However, in an accompanying editorial, Sripal Bangalore and Deepak L Bhatt (J Am Coll Cardiol. 2017;70:3007-9) point out that the findings of this study are in contrast with some of the other recently published studies. A registry from New York reported outcomes in >16,000 diabetics with MV-CAD who underwent PCI using second-generation DES or CABG (Circ Cardiovasc Interv 2015;8:e002626). Short-term results favored PCI with a lower risk of death and stroke, whereas in the long term, PCI was associated with lower risk of stroke and higher risk of repeat revascularization with similar risk of death. ACS patients were included in this registry but were not analyzed separately. The authors of this editorial also performed a meta-analysis of three other large randomized studies (the Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease) (N Engl J Med 2015;372:1204-12.); Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization trial (N Engl J Med 2016;375:2223-35); and Nordic-Baltic-British Left Main Revascularization Study (Lancet 2016;388:2743-52)) that compared PCI using second-generation DES with CABG. These trials had included a variable proportion of patients with ACS (18%–53%), but this meta-analysis did not report outcomes in ACS versus stable CAD patients separately. Furthermore, diabetics were also not analyzed separately. Nevertheless, in the overall study population, PCI was associated with a lower MACE rate at short term and similar MACE rate as CABG at long term. Given these discrepant results, the optimum mode of revascularization in diabetics with MV-CAD will continue to be debated for at least some more time.


  Percutaneous Coronary Intervention in Stable Angina: A double-Blind, Randomized Controlled Trial Top


Al-Lamee R, Thompson D, Dehbi H, Sen S, Tang K, Davies J; on behalf of the ORBITA investigators, et al. Lancet 2017. pii: S0140-6736(17)32714-9.


  Trial Summary Top


Background: Although PCI is considered to be superior to optimized medical therapy (OMT) in relieving anginal symptoms, such benefit has not been proven in any double-blind randomized study. Accordingly, it is not known what proportion of the perceived benefit is actually due to the placebo effect of the coronary intervention.

Methods: In this multicentric study, 230 patients with symptomatic, severe (>70% stenosis) single-vessel CAD were enrolled from 5 different sites in the United Kingdom. Those with angiographic stenosis >50% in a nontarget vessel, ACS, previous CABG, left main stem CAD, contraindications to DES, chronic total coronary occlusion, and/or severe left ventricular systolic impairment were excluded from the study. After enrollment, the patients first underwent 6 weeks of medication optimization, followed by randomization to either PCI arm or a sham procedure arm. In all participants, fractional flow reserve and instantaneous wave-free ratio estimation were done at the time of coronary angiogram. All participants underwent clinical assessment, cardiopulmonary exercise testing, and dobutamine echocardiography before randomization and at 6 weeks after the percutaneous coronary procedure (actual PCI or the sham procedure).

Results: After the initial phase of medical optimization, 200 patients underwent actual randomization (105-PCI, 95-sham procedure). At the time of randomization, the mean number of antianginal drugs was 2.9 in the PCI arm and 3.1 in the placebo procedure arm (P 0.097). Most of the lesions (69%) were in the LAD artery. The lesions had mean area stenosis of 84·4% ± 10·2%, fractional flow reserve of 0·69 ± 0·16, and instantaneous wave-free ratio of 0·76 ± 0·22. In the PCI arm, all patients received DES. At 6 weeks after the procedure, there was no significant difference in the primary end point of exercise time increment between the two groups (28.4 s in PCI arm versus 11.8 s in the placebo arm, P = 0.2). Most of the secondary end points, including time to 1-mm ST depression, peak oxygen uptake, Duke treadmill score, functional class, and angina frequency, also did not show any differential change between the two groups. However, dobutamine-induced wall motion score index showed greater improvement in the PCI arm (from 1.11 before randomization to 1.03 at 6-week follow-up) as compared to the sham procedure arm (from 1.11 to 1.13). There were no deaths. Serious adverse events included four pressure wire-related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group.

Conclusions: In patients with symptomatic, single-vessel CAD, treated with OMT, PCI did not increase exercise time by more than the effect of a placebo procedure.


  Perspective Top


It is a conventional wisdom that compared with medical therapy, PCI is more effective in relieving myocardial ischemia and anginal symptoms. Accordingly, in patients with obstructive CAD who remain symptomatic despite OMT, PCI is a Class I recommendation (provided the coronary anatomy is suitable for PCI). However, these recommendations are based on data derived from studies that did not include a placebo arm as comparator, and therefore, it is not clear what proportion of the observed benefit from PCI is due to the placebo effect. In this context, the ORBITA trial provided useful information. It showed that even in patients with significant obstructive CAD (predominantly LAD artery stenosis with average stenosis severity ~85%), who were treated with OMT, PCI was not more effective than placebo in improving angina. These findings might seem to question the very utility of PCI in the management of stable CAD. However, the results of the ORBITA study need to be viewed in proper perspective. First, only those with single-vessel CAD were included in this study. It is very likely that medical management alone may not prove to be as effective as PCI in patients with MV-CAD. Second, the mean number of antianginal drugs was 3.0 in this study. Many patients might prefer to undergo PCI and reduce the burden of antianginal drugs than to continue on multiple medications. And finally, even in the ORBITA study, PCI did improve the extent of myocardial ischemia as assessed by dobutamine echocardiography. Thus, while the results of ORBITA study reinforce the value of OMT in the management of stable CAD, it seems justifiable to continue to offer PCI to the patients who remain symptomatic despite OMT.


  Percutaneous Coronary Intervention Strategies in Patients With Acute Myocardial Infarction and Cardiogenic Shock Top


Thiele H, Akin I, Sandri M, Fuernau G, de Waha S, Meyer-Saraei R; for the CULPRIT-SHOCK Investigators, et al. N Engl J Med 2017;377:2419-32.


  Trial Summary Top


Background: In patients with acute MI and cardiogenic shock, who are undergoing primary PCI, it remains controversial whether complete revascularization should be done at the time of index procedure or only the culprit lesion should be addressed.

Methods: This trial randomly assigned 706 patients presenting with acute MI with cardiogenic shock with MV-CAD to one of the two initial revascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate MV-PCI. The primary end point was a composite of death or severe renal failure leading to renal replacement therapy within 30 days after randomization.

Results: Median age of the participants in this study was 70 years and nearly three-fourths were men. Triple-vessel disease was present in 63.3% of participants, and the LAD artery was the culprit vessel in 42.0% of participants. Nearly 23.2% of participants had >1 chronic total occlusions. In the MV-PCI group, recanalization of chronic total occlusions was performed when possible, and complete revascularization was achieved in 81.0% of the patients. Staged revascularization was performed in 17.7% of the patients in the culprit-lesion-only PCI group. The crossover rate was relatively low – 12.5% in the culprit-lesion-only PCI group and 9.4% in the MV-PCI group. Ninety-four percent of all the stents implanted in the culprit vessels were DES. The strategy of culprit-lesion-only PCI was associated with a lower incidence of the composite primary endpoint at 30 days (45.9% versus 55.4%; relative risk, 0.83; 95% confidence interval, 0.71–0.96; P = 0.01) [Figure 2]. The culprit-lesion-only PCI was also associated with a lower risk of individual components of the primary end point, with a 16% relative risk reduction in death (P = 0.03) and a 29% relative risk reduction in the need for renal replacement therapy (P = 0.07). The time to hemodynamic stabilization, the need for and the duration of inotropic support, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups.
Figure 2: Clinical outcomes at 30 days in the CULPRIT-SHOCK study. PCI = Percutaneous coronary intervention

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Conclusions: Among patients who had presented with acute MI with cardiogenic shock and had MV-CAD, the 30-day risk of a composite of death or severe renal failure leading to renal replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate MV-PCI.


  Perspective Top


In patients with uncomplicated ST-elevation MI, complete revascularization at the time of initial primary PCI seems to be associated with better clinical outcomes than with culprit-lesion-only PCI. However, in patients with cardiogenic shock, several previous studies have suggested that initial MV-PCI may be associated with greater harm than benefit. The CULPRIT-SHOCK study, being a randomized study, provides compelling evidence to support these observations. The consistency of results across prespecified subgroups and different analytical approaches (intention-to-treat, per-protocol, and as-treated) lends further credibility to the study findings.

There are several mechanisms that may explain greater risk of adverse events with MV-PCI in the setting of cardiogenic shock. Cardiogenic shock results in activation of several deleterious pathways leading to proinflammatory signaling, heightened platelet reactivity, catecholaminic overstimulation, generalized vasomotor dysregulation, oxidative injury, etc., This may predispose to a greater risk of ischemia or infarction, as well as contrast injury, during PCI of nonculprit arteries leading to adverse clinical outcomes.

Financial support and sponsorship

Nil

Conflicts of interest

There are no conflicts of interest.




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