Almanac 2015: coronary artery disease

David M Shavelle

doi:10.15836/ccar2016.188

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Almanac 2015: coronary artery disease

Review Article

Issue5-6

PublishedMay 2016

Pages188-200

PDF via DOIhttps://doi.org/10.15836/ccar2016.188

Authors

David M ShavelleDivision of Cardiovascular Medicine, University of Southern California, Los Angeles, United States of America

Abstract

Summary: Recent years have seen major advances in the evaluation and treatment of patients with coronary artery disease. These include assessment of novel biomarkers and imaging methods for patients at risk for coronary artery disease, care of patients with ST-segment elevation myocardial infarction, a novel device to treat medical refractory angina, use of non-statin lipid-lowering agents, a better understanding of the risks and benefits of longterm dual antiplatelet therapy and the use of the newer antiplatelet agents. This article summarises research related to coronary artery disease published in Heart in 2014 and 2015, within the context of other major cardiovascular journals.

Full Text

First published in Heart [Heart. 2016;102:492-499. DOI: http://dx.doi.org/10.1136/heartjnl-2015-307761 ] and reproduced with permission. Copyright restrictions apply.

Epidemiology

Cardiovascular disease (CVD) remains the main cause of death within industrialised nations. (1, 2) Gender differences exist, and in 2012, CVD was the main cause of death for women within the UK; however, for men, cancer was the main cause of death (Figure 1). (3) Wilmot et al recently reported that mortality secondary to CVD has fallen for adults over the age of 25 years within the USA. However, variation was seen between the rate of fall for various age groups with those <55 years experiencing a smaller relative decrease than older age groups. (4)

Figure 1. Deaths by cause and sex, UK. This figure compiles data from the four countries of the UK. In Northern Ireland, the data for lung cancer only includes International Classification of Diseases-10 code C34. Adapted from England and Wales, Office for National Statistics (2014) Deaths registered by cause, sex and age. http://www.statistics.gov.uk (accessed January 2014); Scotland, National Records of Scotland (2014) Deaths, by sex, age and cause. http://www.gro-scotland.gov.uk (accessed January 2014); Northern Ireland, Statistics and Research Agency (2014) Registrar General Annual Report. NISRA: Belfast. Figure 1 from Bhatnagar et al. (3)

Cardiovascular risk assessment

Although traditional cardiovascular risk factors are useful in evaluating an individual’s risk for future cardiovascular events, contemporary studies have focused on novel risk factors and/or imaging methods in an attempt to improve this risk assessment. Aortic valve calcium is thought to be a manifestation of systemic atherosclerosis and may therefore identify asymptomatic individuals at a higher risk for future cardiovascular events. Using data from the Heinz Nixdorf Recall Study, Kalsch et al (5) evaluated 3944 asymptomatic individuals and measured aortic valve calcium using CT. Over a mean follow-up period of approximately 9 years and after adjusting for traditional Framingham risk factors, those with an aortic valve calcium score >0 had a significantly increased risk for future CVD events. However, when including coronary artery calcium and traditional Framingham risk factors, the presence of aortic valve calcium no longer independently predicted CVD events. Red cell distribution width is a measure of the size variation of red blood cells and is thought to be a novel marker for patients with various manifestations of coronary artery disease (CAD). (6, 7) Borne et al (8) evaluated over 28 000 subjects free of prior CVD and found that a high red cell distribution width was associated with an increased risk for future acute coronary events. Given the premise that atherosclerosis shares many features of other inflammatory diseases, Hsiao et al (9) evaluated patients with chronic osteomyelitis to determine if they had an increased risk for subsequent CVD. Using a national insurance dataset with over 15 000 patients with osteomyelitis, the authors found that the incident rate of CVD was 1.65 times higher, after controlling for cardiovascular risk factors, in those individuals with osteomyelitis. The potential mechanisms linking osteomyelitis and subsequent CVD remain unclear.

Stable CAD

Antiplatelet therapy

Patients with established CAD have an ongoing risk for future cardiovascular events, despite the use of medical therapy. Prior studies evaluating long-term thienopyridine use in patients with established CVD failed to show a benefit. (10) In routine clinical practice, a commonly encountered subgroup of patients with established CAD are those with a prior coronary drug eluting stent (DES). These patients have an inherent, although low, risk for late stent thrombosis and future cardiovascular events. Continuing dual antiplatelet therapy (DAPT) beyond the traditional 12 months may reduce future cardiovascular events; conversely, continued DAPT may be associated with an increased risk of bleeding. The DAPT study evaluated over 9000 patients with a DES and at 1 year randomised patients to continued thienopyridine treatment or placebo in the setting of continued aspirin therapy. (11) In those receiving continued thienopyridine treatment, the risk of stent thrombosis and major adverse cardiovascular and cerebrovascular events was reduced compared with those receiving placebo. However, moderate or severe bleeding events were increased in those receiving continued thienopyridine treatment. The ARCTIC-Interruption trial randomised 1259 patients after 1 year in a similar manner to the DAPT study to continued thienopyridine treatment or placebo and found similar cardiovascular events with increased bleeding events in those receiving thienopyridine treatment. (12) The current literature supports weighing the risks versus benefits of continued thienopyridine treatment after 1 year and individualising treatment recommendations based upon specific patient-related factors. (13)

Non-invasive diagnostic testing

A variety of non-invasive imaging methods are available to evaluate patients with presumed anginal chest pain. (14) The advantages and limitations of each of these non-invasive imaging methods were summarised by Yilmaz and Sechtem (Table 1). (15, 16) In recent years, cardiovascular MRI has experienced the most robust growth and the diagnostic accuracy for identifying obstructive CAD using 3.0 T magnetic resonance scanners is now comparable with single photon emission CT. (17)

Table 1: Comparison of non-invasive imaging modalities table 2 from Yilmaz et al ( 15 ).

Fractional flow reserve

Fractional flow reserve (FFR) provides an invasive means to determine the haemodynamic significance of moderate coronary artery lesions. (18) Randomised trials have shown that use of FFR (FFR-guided) compared with solely relying on the results of coronary angiography (angiography-guided) reduces the need for unnecessary percutaneous coronary intervention (PCI) and decreases future cardiovascular events. (19) Despite these benefits, the adoption of FFR into routine clinical practice has been relatively low likely related to issues of cost and the additional time required to perform FFR measurements as this requires placement of a guidewire to the distal coronary bed. To provide additional information regarding the benefits of FFR, Zhang et al (20) performed a meta-analysis that included four prospective and three retrospective studies with over 49 000 patients. An FFR-guided PCI strategy was associated with a 70% relative reduction in major adverse cardiovascular events (MACE) compared with an angiography-guided PCI strategy. This meta-analysis provides further evidence to support the routine use of FFR in the setting of intermediate coronary artery stenosis in patients being considered for PCI.

Medically refractory angina

The treatment of patients with medical refractory angina remains challenging. (21) Despite the use of newer antianginal therapy (ranolazine), a large number of patients remain highly symptomatic with impaired quality of life. Verheye et al recently reported the use of a novel balloon-expandable device placed within the coronary sinus to cause of a focal narrowing, thereby increasing pressure within the coronary sinus and theoretically redistributing blood flow to ischaemic myocardium. (22, 23) In a small clinical trial of 104 patients with Canadian Cardiovascular Society (CCS) class III or IV angina, use of the device relative to a sham procedure was associated with a marked improvement in CCS angina class.

Vasospastic angina

Although calcium channel blockers are the mainstay of therapy for patients with vasospastic angina, up to 20% of patients may be refractory to treatment and/or experience side effects. The Study to evaluaTe the Efficacy and safety of Pletaal (ciLostazoL) in subjects with vAsospastic angina (STELLA) trial included 50 patients with significant vasospastic angina who remained symptomatic despite amlodipine therapy and randomised them to cilostazol or placebo for 4 weeks. (24) Patients receiving cilostazol therapy had a significant reduction in weekly angina episodes compared with those receiving placebo, 66% vs 18%, p=0.0009, respectively (Figure 2).

Figure 2. Box-and-whiskers plots showing percentage change of weekly chest pain frequency. Chest pain frequency was significantly improved in the cilostazol group compared to the placebo group. Primary endpoint was defined as: (number of angina episodes at baseline week – number of angina episodes at last week)/(number of angina episodes at baseline week)×100. The distribution range signifies the 95% CIs. Mean, rank-ANCOVA with treatment as factor and baseline as covariate (p<0.05). Figure 2 from Shin et al. (24)

Diabetes mellitus and multivessel CAD

Diabetes mellitus is an independent predictor for worse outcome following coronary revascularisation. (25, 26) In addition, the extent of revascularisation (complete vs incomplete) is also thought to be extremely important in the setting of diabetes mellitus. (27, 28) Jimenez-Navarro included over 5000 patients with multivessel CAD undergoing PCI and evaluated the association of diabetes mellitus and complete versus incomplete revascularisation on long-term outcome. (29) Complete revascularisation was associated with significantly improved survival over 10 years (Figure 3). More importantly, patients with diabetes mellitus and incomplete revascularisation had a significantly lower survival compared with their non-diabetic counterparts. These findings suggest that the extent of revascularisation is particularly important in the setting of diabetes mellitus and complete revascularisation should be a goal of therapy.

Figure 3. Unadjusted mortality curves during follow-up for stable disease versus acute coronary syndrome (ACS). CR, complete revascularisation; IR, incomplete revascularisation; PCI, percutaneous coronary intervention. Figure 1 from Jimenez-Navarro et al. (29)

Acute coronary syndromes

Use of thrombectomy

The large-scale randomised Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study (TAPAS) trial showed a benefit of routine thrombectomy prior to coronary stenting with improved myocardial blush grade and lower mortality. (30, 31) Following publication of the TAPAS trial, American College of Cardiology/ American Heart Association/Society Cardiac Angiography and Intervention (ACC/AHA/SCAI) and European Society of Cardiology practice guidelines thus recommended the routine use of thrombectomy during primary PCI for ST-segment elevation myocardial infarction (STEMI). (32, 33) In contrast, the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial found no benefit of routine thrombectomy at 1 year. (34) A meta-analysis of 17 trials with over 20 000 patients also failed to document a benefit of routine thrombectomy. (35) In an attempt to address these conflicting results, Jolly et al (36) enrolled 10 732 patients in the Trial of Routine Aspiration Thrombectomy with PCI versus PCI Alone in Patients with STEMI (TOTAL) and found no reduction in cardiovascular events for patients randomised to routine thrombectomy. In addition, the occurrence of stroke, and in particular ischaemic stroke, was higher in patients receiving thrombectomy (37) (Table 2). At the present time, the current body of literature does not support the routine use of thrombectomy during primary PCI for STEMI and many investigators argue that thrombectomy should be reserved for those with extensive (large) thrombus burden. (38) The 2015 ACC/AHA/SCAI Focused Update on Primary PCI for STEMI downgraded routine aspiration thrombectomy from Class IIa to Class III (no benefit). (39)

Table 2: Summary of clinical trials evaluating the use of thrombectomy for ST-segment elevation myocardial infarction.

Bioresorbable vascular scaffolds

The newest iteration of coronary stents, bioresorbable vascular scaffolds (BVS), has also been evaluated in patients with STEMI. Diletti et al (40) completed one of the initial pilot studies with BVS in 49 patients with STEMI and found high procedural success, excellent stent apposition by optimal coherence tomography and no episodes of target-lesion failure to 30 days. Kocka et al (41) evaluated 141 patients undergoing primary PCI for STEMI and found high procedural success and similar eventfree survival compared with patients receiving bare metal stents.

Multivessel PCI

Current practice guidelines caution against the use of multivessel PCI at the time of infarct-related artery (IRA) revascularisation for patients with STEMI. (39–42) The recently completed Preventive Angioplasty in Acute Myocardial Infarction (PRAMI), Complete versus Lesion-only Primary PCI (CVLPRIT) and Third DANish Study of Optimal Acute Treatment of Patient with ST-segment Elevation Myocardial Infarction: Conventional Primary Angioplasty and Complete Revascularisation versus Treatment of Culprit Lesion only (DANAMI-3-PRIMULTI) trials all found a reduction in cardiovascular events (mainly from fewer repeat revascularisation procedures) for patients underling complete revascularisation during the index event (43–45) (Table 3). A meta-analysis by Kowalewski et al (46) that included seven randomised controlled trials with 1303 patients also found a reduction in major adverse cardiovascular events, recurrent MI and repeat revascularisation for patients receiving multivessel PCI compared with those receiving IRA-only PCI. These clinical studies prompted the 2015 ACC/AHA/SCAI Focused Update on Primary PCI for STEMI to change multivessel PCI during STEMI from Class III to Class IIb. (39) The ongoing Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Primary PCI for STEMI (COMPLETE) study with 3900 patients with STEMI will likely yield the definite answer on the issue of complete revascularisation at the time of IRA PCI versus conservative therapy (only reference available at this time is from http://clinicaltrials.gov/ct2/show/NCT01740479. A high-risk subgroup of patients with STEMI and multivessel CAD are those with cardiogenic shock. Park et al (47) evaluated approximately 16 000 patients participating in a nationwide, prospective registry in Korea to study whether multivessel PCI versus IRA-only PCI was associated with a mortality benefit. After adjusting for confounding factors, multivessel PCI was associated with lower all-cause death both in-hospital and at long-term follow-up, compared with IRA-only PCI.

Table 3: Summary of clinical trials evaluating multivessel percutaneous coronary intervention versus staged percutaneous coronary intervention for patients with ST elevation myocardial infarction and multivessel coronary artery disease.

Reduction in infarction size

Prompt and effective restoration of epicardial coronary flow is the goal of primary PCI and the main determinant of outcome in patients with STEMI. Despite continued advances in the care of patients with STEMI with the use of radial artery access, potent antiplatelet agents and integrated and efficient systems of care, a significant number of patients surviving the acute event experience some degree of myocardial dysfunction and are therefore at increased risk for sudden cardiac death. (48) Strategies directly targeted to limit infarct size have thus been an area of active research. (49) Mechanical methods to augment coronary artery perfusion and reduce afterload with intra-aortic balloon counterpulsation have not shown benefit. (50) The use of supersaturated oxygen therapy has been shown to reduce free radical production and favourably alter components of the inflammatory response during an acute myocardial infarction. (51) The Acute Myocardial Infarction with Hyperoxemic Therapy (AMIHOT-II) trial recently reported a benefit of supersaturated oxygen for patients with an anterior STEMI with a statistically significant reduction in infarct size. (52) Induction of mild hypothermia with various devices in small pilot studies failed to show a consistent benefit. (53, 54) Hypothermia has been used in a variety of clinical settings including out-of-hospital cardiac arrest and during cardiopulmonary bypass; given the benefits seen, interest has grown to use hypothermia either before or during primary PCI for STEMI. (55) The large-scale Rapid Endovascular Catheter Core Cooling Combined With Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction (CHILL- MI) study did not show a reduction in infarct size in those patients randomised to endovascular cooling. (56) However, combining patients from CHILL-MI and an initial safety study called Rapid Intra-vascular Cooling in Myocardial Infarction as Adjunctive to Percutaneous Coronary Intervention (RAPID MI-ICE), there did appear to be benefit for hypothermia with a relative reduction in infarct size of approximately 15%; patients with an anterior STEMI derived even greater benefit. (57)

Unstable angina/non-STEMI

Patients with unstable angina and non-STEMI (NSTEMI) represent a heterogeneous cohort with variable risks for recurrent MI and death. (58) A number of risk scores including Global Registry of Acute Coronary Events (GRACE), TIMI and history, electrocardiogram, age, risk factors, troponin (HEART) and biomarkers have thus been developed to objectively assess these risks to determine best practices for diagnostic testing and use of invasive and medical therapy. (59–63) Patients presenting to the emergency department with presumed cardiac chest pain are common, accounting for approximately 10% of patients evaluated. The ability to identify patients with a low and very low risk for future cardiovascular events who are appropriate candidates for early discharge thus avoiding hospital admission remains challenging. Carlton et al (64) evaluated the use of an accelerated diagnostic protocol using a single high-sensitivity troponin T that was drawn at hospital presentation and the modified Goldman risk score. Among the cohort of 960 patients, the accelerated diagnostic protocol identified approximately 40% that were suitable for early discharge with only one patient (0.3%) experiencing a non-fatal MI within 30 days.

Lipid-lowering therapy

Previous studies evaluating the non-statin drug ezetimibe found dramatic reductions in low-density lipoprotein (LDL) cholesterol levels, but failed to show any benefit on surrogate markers of atherosclerosis, including carotid-artery intima-media thickness. (65) In contrast, the recently reported Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) enrolled over 18 000 patients with an acute coronary syndrome and found a significant reduction in the combined cardiovascular endpoints of cardiovascular death, non-fatal myocardial infarction, unstable angina requiring hospitalisation, coronary revascularisation and non-fatal stroke in those receiving combination therapy with simvastatin and ezetimibe. (66) This trial is highly relevant as it was the first to show an incremental clinical benefit of adding a non-statin agent to standard statin therapy. Using intravascular ultrasound (IVUS) imaging, intensive statin therapy has been shown in multiple clinical trials to cause coronary plaque stabilisation and/or plaque regression. (67, 68) The Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound (PRECISE-IVUS) study found similar findings with combined atorvastatin and ezetimibe; that is, combination therapy was associated with lower levels of LDL cholesterol and greater coronary plaque regression, compared with monotherapy with atorvastatin alone. (69) In comparison with the aforementioned studies using IVUS and various statins to assess for plaque regression, combination therapy with atorvastatin and ezetimibe achieved the most significant plaque regression seen to date (2.3% reduction in plaque atheroma volume).

Antiplatelet therapy

Despite extensive experience with the second-generation thienopyridine clopidogrel, limitations in bioavailability, onset of action and efficacy spurred the development of the newer generation agents, prasugrel and ticagrelor. (70, 71) Studies suggest that use of these agents in contemporary practice is approximately 30%, although regional and national variations exist. (11) In the TRial to Assess Improvement in Therapeutic Outcomes by Optimising Platelet InhibitioN with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) prasugrel was associated with excessive-bleeding events in patients with a prior transient ischaemic accident or stroke, those older than 75 years and those with body weight <60 kg. (72) Data regarding bleeding events with prasugrel compared with clopidogrel outside of randomised trials is limited. Klingenberg et al (73) evaluated 2286 patients with acute coronary syndromes, applied propensity score methodology and compared bleeding events between those receiving clopidogrel and prasugrel. For patients at increased risks for bleeding, the reduced maintenance dose of 5 mg of prasugrel was studied. At 1 year, bleeding events were similar between the two agents; that authors noted that the study was not designed to compare efficacy. Ticagrelor was the first antiplatelet agent to demonstrate a reduction in 1-year mortality in patients with ACS in the PLATelet inhibition and patients Outcome (PLATO) trial. (74) In a detailed evaluation of all causes of vascular and overall death events in the PLATO trial, Varenhorst et al (75) found the mortality benefit of ticagrelor was mediated by a reduction in sudden death events. The mechanism for this remains unclear but is thought to be related to potential pleiotropic effects of ticagrelor.

Out-of-hospital cardiac arrest

Recent practice guidelines recommend consideration of early coronary angiography in patients with out-of-hospital cardiac arrest. (33, 76) The decision to proceed with early angiography is relatively straightforward in patients with an initial shockable rhythm, those with a short time from cardiac arrest to resuscitation and those with ST-segment elevation on the postresuscitation ECG (Figure 4). Management options become challenging in those without clear ST-segment elevation on the postresuscitation ECG, those with an initial unshockable rhythm and those with various predictors of poor neurological outcome, including advanced age (>85 years), use of ongoing cardiopulmonary resuscitation, absence of bystander cardiopulmonary resuscitation and end-stage renal disease. (77)

Figure 4. Proposed treatment algorithm based upon the postresuscitation electrocardiogram (ECG) in patients with out-of-hospital cardiac arrest. Figure 2 from Nerla et al. (78) CCU,coronary care unit; CT, computed tomography; ED, emergency department; ER, emergency room; ITU, intensive care unit.

Acknowledgments

Provenance and peer review Commissioned; internally peer reviewed.

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