Key Points:

• Early high-intensity statin therapy is standard of practice in acute STEMI patients, but this is often insufficient to achieve LDL targets. PCSK-9 therapy has never been tested as routine therapy in STEMI.
• In the EPIC STEMI trial, routine PCSK-9 initiation in addition to high-intensity statin prior to primary PCI resulted in a 22% LDL reduction at 6 weeks relative to sham, with a higher proportion of patients achieving therapeutic LDL targets.

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A recent trial by Dr. Salim Yusuf, published in The New England Journal of Medicine, indicated that combination therapy with aspirin plus a polypill (consisting of a statin plus three blood-pressure-lowering drugs) can reduce the incidence of cardiovascular events compared with placebo among participants without established cardiovascular disease, but at moderate cardiovascular risk.

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A recent trial by Dr. Jordana B Cohen, published in The LANCET, indicated that consistent with international society recommendations, patients admitted to the hospital with COVID-19 can safely continue treatment with renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB)) unless there is a distinct medical contraindication to ongoing therapy.

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Results of the DAPA trial, published in Circulation: Arrhythmia and Electrophysiology, demonstrated that the use of early prophylactic implantable cardioverter defibrillator (ICD) in high-risk post-primary percutaneous coronary intervention (PCI) patients was associated with lower all-cause and cardiac mortality rates. However, the results of this trial should be interpreted with caution, since the trial was stopped prematurely.

The optimal timing of ICD implantation in STEMI patients treated with primary angioplasty is not identified yet. Previous clinical trials have failed to show the benefit of early ICD implantation (4-60 days) in post-MI patients with a low left ventricular ejection fraction (≤35-40%). The risk of sudden cardiac death (SCD) is high within the post STEMI period.  However, ICD implantation after 40 days may not be indicated due to left ventricular remodeling and a potential increase in LVEF post-primary PCI. The Defibrillator After Primary Angioplasty (DAPA) trial evaluated all-cause and cardiac mortality of patients undergoing early prophylactic ICD implantation after PCI for STEMI. Following a recommendation from the data safety board, the trial was terminated early after just 38% of the planned sample size was enrolled due to slow enrollment.

This multicenter, randomized, controlled trial included patients with STEMI who had undergone primary PCI and met at least one of the following criteria: LVEF<30% within 4 days after admission, primary ventricular fibrillation (VF) within 24 hours (during PCI excluded), signs of heart failure on admission (Killip class ≥ 2), and/or thrombolysis in myocardial infarction (TIMI) flow post PCI < 3. The participants were randomized in a 1:1 ratio to receive either ICD implantation or conventional therapy within 30 to 60 days of the STEMI event. The primary endpoint was all-cause mortality at 3 and 9-years. The secondary endpoints of the study included the incidence of sudden cardiac death (SCD) and hospital admission for sustained ventricular tachyarrhythmias or appropriate ICD therapy.

A total of 266 patients with primary PCI for STEMI were included in the study with 131 patients allocated to the ICD arm and 135 patients assigned to the conventional therapy arm. After 3-years of follow-up, the primary outcome of interest was significantly lower among patients who received ICD implantation (5%) compared to the conventional therapy group (13%) (Hazard ratio (HR):0.37; [95% CI: 0.15-0.95]; p=0.04). This result remained similar at a median of 9-years follow-up (HR: 0.58; [95% CI: 0.37-0.91]; p=0.02). In terms of cardiac mortality, ICD implantation was associated with fewer deaths (11%) compared to the control group (22%) (HR: 0.52; [95% CI: 0.28-0.99]; p=0.04). Although not statistically significant, the incidence of SCD was also lower in the ICD group (3.1%) compared to the control group (5.9%) (HR 0.45; [95% CI 0.14–1.50]; p=0.19).

The results of this study should be interpreted with consideration of the following limitations. First, the premature termination of the study makes it underpowered for analysis. Second, the study used more than one inclusion criteria, so results should be interpreted with consideration of the patient characteristics. The high treatment crossovers (10.2%) within the first 3 years of the study and the lack of information on treatment crossovers between 3 and 9 years are additional limitations of the trial.  Furthermore, while pharmacotherapy of the participants was similar at baseline, there is a lack of data regarding the follow-up medical therapy which may have impacted the mortality rates.

In conclusion, this prematurely terminated trial suggests that early prophylactic ICD implantation may be associated with a better survival rate in patients at high risk of death after primary PCI for STEMI. The results of this trial should be confirmed in future studies.

A trial by Dr. Jorrit S. Lemkes, published in JAMA Cardiology, demonstrated that immediate coronary angiography and percutaneous coronary intervention (PCI) does not improve the 1-year clinical outcomes of patients after successful resuscitation from non-ST segment elevation cardiac arrest. Also, the survival rate was comparable between patients whose angiography was performed immediately (61.4%) versus those whose angiography was delayed (64.0%).

Given the high prevalence of coronary artery disease among patients with cardiac arrest, coronary angiography and PCI should be considered in these patients with suggested evidence of coronary artery involvement. However, the current data regarding the appropriate timing of this intervention is lacking. The interim results of the Coronary Angiography after Cardiac Arrest (COACT) trial failed to find a significant difference between the 90-days clinical outcomes of patients with delayed coronary angiography versus patients with immediate coronary angiography after non-ST segment elevation cardiac arrest. The 1-year follow-up study investigated the long-term clinical outcomes of immediate coronary angiography in these patients.

COACT study, an open-label, multicenter, randomized trial, compared the short-term clinical outcomes of immediate versus delayed coronary angiography in patients resuscitated from cardiac arrest without ST-segment elevation on the electrocardiogram tracing. Briefly, a total of 552 patients with out-of-hospital arrest and no signs of ST-segment elevation myocardial infarction (STEMI) who successfully resuscitated from cardiac arrest were randomized in a 1:1 ratio to undergo immediate (within 2 hours of randomization) or delayed (after neurological recovery or discharge from intensive care unit) coronary angiography. The 1-year endpoints of the study included survival rate, myocardial infarction, repeated revascularization, hospitalization for heart failure, and implantable cardiac defibrillator (ICD) shock since the index hospitalization.

At 1-year follow-up, 94.6% of the participants (n=522) were available for analysis. The recent analysis of the data indicated no significant differences between the two groups. The survival rate was 61.4% and 64.0% in the immediate and delayed coronary angiography group, respectively (odds ratio (OR)=0.90; 95%Confidence Interval (CI):0.63-1.28). Additionally, the endpoints of the interest were equivalent in the 2 groups. For example, the rate of myocardial infarction was 0.8%in the immediate group and 0.4%in the delayed group (OR=1.96; 95%CI: 0.18-21.8). The study also showed that the post-cardiac arrest mortality usually occurs within the first 90 days after the arrest, and the survival rate after this period is relatively favorable.

The trial has some limitations that need to be taken into account. First, the study is not powered for a 1-year analysis. Second, the findings of this study are not generalizable to patients with shock, severe renal dysfunction, or persistent ST-segment elevation due to their exclusion from the trial.

The results of this trial suggest that in patients with out-of-hospital cardiac arrest with no signs of STEMI, the coronary angiography, if necessary, can be delayed until after neurological recovery.

A recent study by Dr. Banerjee, published in Circulation: Cardiovascular Interventions, demonstrated the efficacy and safety of low-density lipoprotein (LDL) lowering therapy via a single LDL apheresis treatment plus ongoing statin therapy in nonfamilial hyperlipidemia acute coronary syndrome patients treated with the percutaneous coronary intervention (PCI).
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The post hoc analyses of GLOBAL LEADERS study by Dr. Hara, published in Circulation: Cardiovascular Quality and Outcomes reported that in multiple statistical analyses considering the total number and severity of bleeding and ischemic events, ticagrelor monotherapy consistently decreased the risk of these events by 5% to 8% compared to 1-year conventional dual antiplatelet therapy. This analysis supported the beneficial effects of ticagrelor monotherapy after percutaneous coronary intervention. Continue reading →

A recent meta-analysis of clinical trials with more than 100,000 patients has shown that the carotid intima-media thickness (cIMT) progression can be used as a surrogate marker for cardiovascular risk in the clinical trials. The results of this study published in Circulation. According to Dr. Willeit, the assessment of cIMT progression can provide a link for the development and license of new therapies for cardiovascular disease. Continue reading →

A recent study by Dr. Julinda Mehilli, M.D., published in Circulation journal, has shown that in patients undergoing elective percutaneous coronary intervention (PCI), pretreatment strategy with the intensified prasugrel loading does not differ from standard clopidogrel loading dose in terms of Safety and Efficacy. According to the trial, both strategies can be safely applied among patients undergoing elective PCI.
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A recent study by Dr. Mehra, published in the New England Journal of Medicine, disapproved of the previously concerning idea regarding the potential harmful effect of angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) in the clinical context of Coronavirus disease 2019 (Covid-19). This study also demonstrated that Covid-19 may disproportionately affect individuals with cardiovascular disorders.
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The results of a pooled analysis of the ORION-10 and ORION-11 trials were recently presented at the American College of Cardiology 2020 Conference. The combined results published in the New England Journal of Medicine, demonstrated that inclisiran, a drug that inhibits hepatic synthesis of proprotein convertase subtilisin–kexin type 9, reduced low-density lipoprotein (LDL) cholesterol by 50% over 510 days.

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In an original investigation done by Dr. Alexander C. Fanaroff et al and recently published in JAMA Cardiology, it was found that there was discordance in medication persistence as measured by patient-reported and the pharmacy fill data. The patient self-reports overestimated and pharmacy fill data underestimated medication persistence. Those who had non-persistence by both measures had the highest rate of major adverse cardiovascular events (MACE). The authors also noted the need for giving preference to interventions that will promote medication-taking behavior. Continue reading →

In an original investigation by Dr. Alexander R. van Rosendael et al recently published in JAMA Cardiology, it was found that the higher-density calcified plaque, referred to as 1K plaque was associated with a reduced risk for future Acute Coronary Syndromes (ACS). The authors also support the hypothesis of plaque stabilization with coronary calcium with the results of this analysis of Incident Coronary Syndromes Identified by Computed Tomography (ICONIC) study and are considerate of different risk stratifications that can be detected in atherosclerotic plaque beyond its burden. Continue reading →

A post-hoc analysis of the Drug-Eluting Stents Versus Bare-Metal Stents in Saphenous Vein Graft Angioplasty (DIVA) trial was recently published in Circulation: Cardiovascular Interventions. The study led by Dr. Faisal Latif showed that in patients undergoing percutaneous coronary intervention (PCI) of a de novo saphenous vein graft lesion, there was no difference in target vessel failure at 12 months between the stent-only and balloon-stent group. However, stent thrombosis and target vessel myocardial infarction (MI) rates were lower in the stent-only group over a longer duration of follow up.

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In a recent randomized, three-arm, parallel, blinded study by Dr. Schnorbus, published in European Heart Journal, prasugrel was associated with improved endothelial function, more potent platelet inhibition, and decreased plasma interleukin (IL)-6 levels in patients undergoing stent placement for acute coronary syndrome (ACS) compared to ticagrelor and clopidogrel. These effects were observed in patients who received prasugrel 2 hours before stenting.

Coronary artery stenting has been associated with impaired coronary and peripheral endothelial function as well as an inflammatory response leading to the release of mediators and subsequent platelet aggregation. These phenomena are associated with in-stent restenosis as well as adverse prognostic outcomes after percutaneous coronary intervention (PCI). Platelet inhibitors, such as P2Y12 receptor inhibitors, are administered prior and after coronary interventions to address these adverse effects. However, previous studies have suggested that differences exist among P2Y12 inhibitors in terms of their efficacy.

In a prospective, single-center study, a total of 90 patients with unstable angina or non-ST elevation myocardial infarction (NSTEMI) undergoing coronary stenting were randomized to receive a single dose of clopidogrel (600mg), prasugrel (60mg), or ticagrelor (180mg) followed by chronic therapy with the same drug. Patients with elevated c reactive protein (CRP), infective or inflammatory disorders, personal history of prior coronary interventions, impaired hepatic/renal function, those with heart failure, and those with ST elevation myocardial infarction (STEMI) were excluded from the study. The primary endpoint of the study was the change in flow-mediated dilation (FMD) of the conduit artery over a period of 1 day, 1 week, and 1 month after PCI. Secondary endpoints were the effect of study medications on macrovascular and microvascular function, platelet aggregation, and inflammatory stress.

The study showed that antiplatelet therapy immediately before stenting was associated with improved FMD without a significant difference among study medications. On the first follow-up after PCI and later follow-up visits, prasugrel was associated with a stronger platelet reactivity inhibition and improved endothelial function. These effects were limited to those who received prasugrel before catheterization. Prasugrel platelet inhibitory effect was more obvious in NSETMI patients than in those with unstable angina. Prasugrel therapy also led to a more pronounced decrease in IL-6 levels. According to the author, “when administered pre-PCI, prasugrel, but not the other agents, limits stent-induced endothelial dysfunction and inflammation in ACS.” This study is limited by its small size and future studies are needed to further confirm these conclusions.

The sympathetic drive leading to the release of arrhythmogenic agents after myocardial infarction (MI) is the target of pharmacologic treatment to reduce the mortality associated with post-MI arrhythmias. Beta-blockers, so far, are the only primary prevention antiarrhythmic drugs that decrease the mortality following MI.  However, ventricular arrhythmias still complicate up to 10% of the cases despite sufficient beta-blockade. Additionally, MI has been associated with the release of non-catecholaminergic co-transmitters such as neuropeptide Y (NPY). This cardiac sympathetic co-transmitter can affect calcium electrophysiology of the cardiomyocytes and trigger arrhythmic events.

The new study by Dr. Kalla and his colleagues hypothesized that NPY is the pro-arrhythmic agent after an MI. To evaluate their hypothesis, they monitored 78 patients with ST-elevation MI  treated with primary percutaneous coronary intervention (PPCI) for the development of ventricular arrhythmias. Peripheral venous blood sampling was done at the time of intervention to assess the NPY level. To compare, they also measured the NPY level of peripheral venous blood in 12 candidates of elective angiography of similar age and gender, who had normal coronary arteries.

Ventricular arrhythmias occurred in 7% of the STEMI patients within 48 hours. Their venous NPY level has observed to be significantly (P < 0.05) higher compared to control patients. The author also suggested that an NPY level of 27.3 pg/mL has a sensitivity of 0.83 and a specificity of 0.71 for ventricular arrhythmias threshold. To further evaluate their hypothesis regarding the arrhythmogenic effect of sympathetic-induced NPY release, they experimented with an animal model. Through their rat model experiment, Dr. Kalla demonstrated that despite maximal beta-blockade with metoprolol, prolonged stimulation of the sympathetic system caused an enormous increase in NPY level and subsequent decrease in ventricular arrhythmias threshold. Interestingly, NPY, antagonized by Y1 receptor antagonist BIBO3304, prevented these effects.

The authors added, ” In patients presenting with STEMI treated with PPCI, NPY levels are associated with an increased incidence of ventricular arrhythmia in the immediate postinfarct period, independent of classical risk factors, such as late presentation, larger infarct size, and prior beta-blocker usage.” The author concluded that sympathetic-induced release of NPY is associated with post-MI arrhythmia and drugs reversing its effect work along with beta-blockers as a new anti-arrhythmic therapy.

A study led by Dr. Mengyu Fan published in the European Heart Journal showed that a healthy sleep pattern was associated with a lower risk of cardiovascular disease (CVD), congestive heart failure (CHF), and stroke in patients with low, intermediate or high genetic risk.

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In patients with stable coronary artery disease, a decrease in circulating progenitor cell count during exercise is associated with worse disease prognosis compared to the presence of stress-induced myocardial ischemia. The study led by Dr. Kasra Moazzami that was published in JAMA Cardiology highlights the need to identify whether strategies to improve circulating progenitor cell count response during exercise will lead to a better prognosis.

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A study led by Dr. Navakaranbir Bajaj published in Circulation showed that coronary microvascular dysfunction, but not estimated glomerular filtration rate was associated with abnormal cardiac mechanics and an increased risk of cardiovascular events. The findings of this study suggest that coronary microvascular dysfunction may play a role in determining how chronic kidney disease can lead to abnormal cardiac function in patients without ischemic heart disease.

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The results of the COMPLETE Optical Coherence Tomography Substudy were presented by Dr. Natalia Pinilla-Echeverri at the American Heart Association 2019 meeting. The substudy found that in patients with an ST-elevation myocardial infarction and multivessel coronary artery disease, half of the patients had a non-culprit lesion with vulnerable plaque morphology.

The COMPLETE trial previously demonstrated that routine angiography guided staged a percutaneous coronary intervention (PCI) of non-culprit lesions reduced the composite endpoint of cardiovascular death or myocardial infarction by 26%. However, whether the benefit of routine PCI of non-culprit lesions is, as a result, the non-culprit lesions having characteristics that were consistent with a vulnerable plaque is not known. Optical coherence tomography (OCT) is a form of intracoronary imaging that is able to identify vulnerable plaques. OCT is able to recognize thin cap fibroadenoma (TCFA), an indicator of a vulnerable plaque that is at risk of rupturing. The investigators wanted to identify the prevalence of TCFA in obstructive compared to non-obstructive non-culprit lesions.

In the COMPLETE trial, patients with a STEMI and multivessel disease who underwent successful PCI of the culprit lesion were randomized to either routine staged PCI of all suitable non-culprit lesions with the goal of complete revascularization regardless of whether there were clinical symptoms or evidence of ischemia or culprit-lesion revascularization only. Patients were deemed to have multivessel disease if they had angiographically significant non-culprit vessel disease of a vessel that was at least 2.5mm in diameter. A lesion was considered angiographically significant if it had at least 70% stenosis of the vessel diameter or 50-69% stenosis with a fractional flow reserve of less than 0.8. In this substudy, STEMI patients with stenosis of at least one non-culprit vessel with more than 70% stenosis that was suitable for OCT were identified. After randomization, multivessel OCT imaging was performed on vessels with non-culprit lesions that underwent PCI, additional vessels with or without target non-culprit lesions for PCI, and STEMI vessels with segments more than 50mm that were unstented.

A total of 93 patients and 425 lesions were included in this substudy. The baseline characteristics in the main study were similar to this imaging study. The average age was 61.3, 82.8% were male, 12.9% had diabetes, 64% had 1 residual diseased vessel and 36% had two or more residual diseased vessels. The non-culprit lesions were classified according to whether they had significant stenosis and whether they had a TCFA. Of the lesions with greater than 70% obstruction, 58 (38.7%) had a TCFA and 92 did not. Of the lesions with less than 70% obstruction, 74 (23.2%) had a TCFA and 201 did not. When assessing the prevalence of TCFAs per patient, the investigators found that half of the patients with TCFA had an obstructive non-culprit lesion that contained vulnerable plaque.

In an interview with Dr. Arzu Kalayci, Dr. Pinilla-Echeverri discussed the implications of the study. She said, “this is very important in the STEMI population because we believe the STEMI population has higher rates of future cardiovascular events. IT may all be related to the inflammatory response that is behind [this]. This is telling us that these patients had a definitely higher risk because they had vulnerable plaques far from the culprit segment. This is reassuring that acute coronary syndrome implies a diffuse pathophysiology with vulnerable plaque not only in the culprit segment but in places far away from the culprit lesion. These results support the findings in the COMPLETE trial.” However, this study does have its limitations. The substudy was observational and is affected by confounding and bias. The substudy was not powered to link clinical evens to morphology. Regardless, the findings of this study could potentially explain the benefit of routine PCI of obstructive non-culprit lesions in patients with STEMI and multivessel disease.

Click here to view the study slides.

Click here to listen to Dr. Kalayci and Dr. Pinilla-Echeverri.