Cover Story: Planet Med, A Globetrotter’s Tour of What’s New in Cardiology | Rick McGuire and Debra L. Beck
CardioSource WorldNews | Rome was terrific, but the heat was nearly unbearable, transportation a major headache, and the convention center struggled to accommodate such a large meeting. Those are the topline results of ESC.16. (Despite the weather and logistic challenges, admittedly having the Pope speak on the final day is not a typical spotlight guest.) As for the European Society of Cardiology meeting itself, it was an interesting mix of international papers and a clear demonstration of the world medical research community. Even the interventional AMERICA trial was French. Here is a guided tour of highlights from Rome. And, like the food in Rome, you’ll find something.
PACIFIC: A Sea Change in Imaging?
For patients presenting for the first time with indications of coronary artery disease, there a number of imaging options. Indeed, in both U.S. and European guidelines, there is little consensus about the choice of non-invasive imaging modality; in general, the guidelines do not advocate for any one imaging technique over another.
In the first head-to-head comparison of the most commonly used non-invasive techniques, investigators evaluated positron emission tomography (PET), single photon emission computed tomography (SPECT), and coronary computed tomography angiography (CCTA) for evaluating myocardial perfusion or coronary artery stenosis severity.
PACIFIC (Prospective Head-to-Head Comparison of Coronary CT Angiography, Myocardial Perfusion SPECT, PET, and Hybrid Imaging for Diagnosis of Ischemic Heart Disease using Fractional Flow Reserve as Index for Functional Severity of Coronary Stenoses) was a single center study of 208 patients with suspected CAD. All patients underwent invasive coronary angiography to assess intracoronary pressure (fractional flow reserve).
Patients then underwent noninvasive PET, SPECT and CCTA as well as some “hybrid” combinations of PET and CCTA or SPECT and CCTA, designed to combine functional and anatomical assessments. Compared to the gold standard invasive test, PET was significantly more accurate (85%) for diagnosing coronary ischemia versus CCTA (74%, p < 0.01) and SPECT (77%, p < 0.01).
Interestingly, diagnostic accuracy was not enhanced by either hybrid CCTA/SPECT or CCTA/PET; instead, they resulted in more false negatives and a decrease in false positive results (p < 0.001). According to Ibrahim Danad, MD (VU University Medical Center, Amsterdam), “The results will definitely spark further research. There is always a lot of discussion whether we need to choose SPECT or PET as the initial functional test for our patients. I think that we need to invest more in clinical PET imaging, which will be future. It is more convenient for patients in terms of time, accuracy and radiation dose.” – European Heart Journal
NIPPON: More Support for Shorter DAPT
Limiting the length of dual antiplatelet therapy (DAPT) gains some ground, this time from the NIPPON (NoborI dual antiplatelet therapy as aPPrOpriate DuratioN) study, which had broad inclusion criteria to reflect the real-world clinical setting. In 3,775 patients with coronary artery disease (CAD) or acute myocardial infarction (AMI) undergoing stenting, there were similar rates of “net adverse clinical and cerebrovascular events” – the main outcome – with either 6- or 18-months of DAPT.
“Based on these findings, a combination of short DAPT and a newer DES with bioabsorbable abluminal coating should be able to minimize the incidence of thrombotic events and bleeding complications simultaneously,” said Masato Nakamura, MD, PhD, of Toho University Ohashi Medical Center in Tokyo, Japan.
NIPPON lends support to a recent systematic review of DAPT data1 and updated guidelines.2 Overall, the evidence now provides what the authors of the systematic review called “moderately strong evidence” that prolonged DAPT after implantation of newer-generation DES entails a tradeoff between reductions in stent thrombosis and MI with increases in major hemorrhage.
In trying to decide who gets what length of DAPT, a world tour of data shows how complexity plays into decision-making: A study of almost 9,600 patients used pooled patient-level data from 6 randomized controlled trials. (Investigators spanned the globe: United States, Italy, Spain, the Netherlands, South Korea, and France.) Of the pooled population, 1,680 (17.5%) patients underwent complex PCI, defined as at least one of the following features: 3 vessels treated, > 3 stents implanted, > 3 lesions treated, bifurcation with 2 stents implanted, total stent length > 60 mm, or chronic total occlusion. The primary efficacy endpoint was major adverse cardiac events (MACE), defined as the composite of cardiac death, MI, or stent thrombosis. The primary safety endpoint was major bleeding.
Patients who underwent complex PCI were at a substantially higher risk of ischemic events, in a graded fashion, with increased procedural complexity (hazard ratio [HR]: 1.98; p < 0.0001) (FIGURE). The risk was similar in magnitude to that of other well-established clinical risk factors and tended to be greater for progressively higher degrees of procedural complexity.
In patients who underwent complex PCI, compared with a short period of DAPT (3 or 6 months), long-term DAPT (> 1 year) significantly reduced the risk of cardiac ischemic events with a magnitude that, again, was greater for higher procedural complexity (adjusted HR: 0.56 for longer DAPT). Compared to the noncomplex PCI group, the p value for interaction was 0.01.
The benefits of prolonged DAPT appeared to be uniform across complex PCI components, DES generations, and clinical presentation. And, of course, long-term DAPT was associated with an increased risk of major bleeding that was irrespective of procedural complexity.
Currently, clinical decision making on upfront DAPT intensity and duration after coronary stenting is predominantly made on the basis of clinical ischemic and bleeding risk factors. Gennaro Giustino, MD, and colleagues are arguing that degree of procedural complexity “substantially influences future ischemic risk and identifies patients who may benefit from longer or more intense antithrombotic therapies.”
Stephan Gielen, MD (University of Leipzig, Heart Centre, Germany) emphasized that the evidence does not suggest a one-size-fits-all approach, but certainly options now exist. He said, “We have new stents with abluminal coating that reduce thrombotic risk. On the other hand, we have very high risk patients with multivessel disease, multi-stents, and older stents where the thrombotic risk may be very high. So, today, a more individualized approach to dual-antiplatelet therapy is more important than ever.” – Journal of the American College of Cardiology (For Giustino et al., Efficacy and Safety of Dual Antiplatelet Therapy After Complex PCI)
In NSTEMI, Aggressive is Better
Even after non-ST elevation myocardial infarction (NSTEMI), aggressive use of percutaneous coronary intervention (PCI) and stenting makes a big difference in achieving positive outcomes, according to the results of an analysis of nearly 400,000 NSTEMI patients living in England and Wales.
Marlous Hall, PhD, from the University of Leeds, England, and colleagues analyzed data from the Myocardial Ischemia National Audit Project (MINAP) from 2003-2004 to 2012-2013. Over this period, fewer patients had intermediate-to-high GRACE risk scores (decreasing from 87.2% to 82.0%) and the proportion of patients at the lowest risk increased (4.2% to 7.6%; p = 0.01 for trend). As you remember, the GRACE score incorporates age, cardiac arrest, ST-segment deviation, biomarker elevation, blood pressure, heart rate, heart failure, and renal function.
Improvements in baseline GRACE risk scores through the years had strong opposing forces: higher rates of diabetes, hypertension, cerebrovascular disease, chronic obstructive pulmonary disease, chronic renal failure, a previous invasive coronary strategy, and current or ex-smoking status compared to earlier years (all p < 0.001).
During the study period, use of guideline-indicated care increased, as did increased use of an invasive coronary strategy (even after adjusting for changes in clinical risk and pharmacological therapies), and patients experienced a significant decrease in 180-day all-cause mortality (10.8% to 7.6%). In analyzing the reasons for the improved outcomes, investigators found that the reduction in baseline acute coronary syndrome (ACS) risk, increase in comorbidities, and use of guideline-indicated therapies did not fully explain the relative 3.2% year-by-year increase in 6-month survival rate throughout the study period.
As seen in international registries, these improvements were significantly and independently associated with use of an invasive coronary strategy, with coronary angiography, PCI, or coronary artery bypass graft (CABG) surgery increasing overall from 42.7% to 78.6% during the course of the study (p < 0.001). – JAMA
Time to Rethink ICDs in HF?
For primary prevention, implantable cardioverter–defibrillators (ICDs) reduce the risk of premature death among patients with left ventricular systolic dysfunction after MI and among patients with heart failure (HF) and reduced ejection fraction. What about patients with HF without CAD?
The guidelines support ICDs in this setting, although based on less robust evidence, for sure; specifically, the evidence comes from a meta-analysis of small trials involving patients with nonischemic cardiomyopathy, as well as subgroup analysis of patients with nonischemic cardiomyopathy from larger trials.
A new study – more than twice the size as the largest previous study – questions this approach. The Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH), randomly assigned 1,116 patients with nonischemic HF to conventional therapy or an ICD plus conventional therapy. After a median of 5.6 years, ICD therapy was associated with a risk of sudden cardiac death that was half that of conventional therapy, but the effect on overall mortality, the primary endpoint of the trial, was not significant.
Importantly, background therapy was really optimized in DANISH, with almost universal use of angiotensin-converting enzyme inhibitors and beta-blockers. Also, patients with nonischemic cardiomyopathy have lower rates of sudden cardiac death and of death from any cause than do patients with ischemic HF. Moreover (and unlike previous ICD trials), 58% of patients received cardiac resynchronization therapy (CRT).
In an accompanying commentary to the published data, John J.V. McMurray, MD, noted that ICDs are expensive and not without adverse effects, meaning they should be avoided in patients who are unlikely to obtain a worthwhile benefit.
In a press conference, Mariell Jessup, MD, Hospital of the University of Pennsylvania and the Presbyterian Medical Center of Philadelphia, said “This is the first trial looking at the use of ICDs in the setting of modern therapy so I think this was really an appropriate trial.” However, she said the big problem we have today is this: not enough ICDs are being used in patients with reasonable life expectancy. She said, “No country is putting in enough ICDs for patients who can expect to live more than 1 year.” – New England Journal of Medicine
Eliminating Lifetime Risk of CVD
A new Mendelian randomization study shows that individuals with lifelong low levels of both low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) have an 86% lower risk of major cardiovascular events. What’s the rub? Well, observational studies have demonstrated that only about 5% of people are able to maintain ideal risk factor profiles throughout adulthood.
In a Mendelian study design, also called a “naturally randomized trial,” genetic scores are used as both the instrument of randomization and the instrument of exposure.
Brian A. Ference, MD, MPhil (Wayne State University, Detroit, MA), and colleagues used genetic and risk factor data from 102,773 people who had participated in 14 prospective cohort or case-control studies to test the causal effect of combined exposure to lower LDL-C and lower SBP. They calculated genetic scores for each patient based on inherited polymorphisms known to be associated with LDL-C or SBP and the number of alleles associated with raised LDL-C or SBP levels.
Participants were then divided into 4 groups: a reference group (above median genetic score), a group with an LDL-C genetic score below the median (resulting in lower LDL-C), a group with a SBP genetic score below the median (resulting in lower SBP), and a group with both LDL-C and SBP genetic scores below the median (resulting in both lower LDL-C and lower SBP).
Compared to the reference group, subjects in the lower LDL-C group had 54.2% lower risk of the primary outcome (OR [odds ratio]: 0.458); those in the lower SBP group had 44.7% lower risk (OR: 0.553); and those in the combined lower LDL-C and SBP group had 86.1% lower risk (OR: 0.139).
Said Dr. Ference: “A simple strategy that encourages long-term exposure to the combined reduction of both 1 mmol/L (38.66976 mg/dl) in LDL cholesterol and 10 mm Hg SBP has the potential to largely eliminate the lifetime risk of cardiovascular disease and cardiovascular events.”
Commenting on the outsized benefit reported, Thierry Gillebert, MD, PhD, (Ghent University, Ghent, Belgium) said the results show that, in this case, “one plus one equals 2.5…”
Age is No Excuse
Low levels of physical activity have reached pandemic proportions, contributing to >5 million deaths each year worldwide, making it 1 of the 10 leading causes of death and disability. We know physical activity is valuable for cardiovascular disease prevention among working age population. What about the elderly?
A Finnish team conducted a prospective cohort study of > 2,400 men and women aged 65 to 74 years who participated in a baseline risk factor survey between 1997 and 2007. After a median follow-up of 11.8 years, moderate- and high-levels of physical activity level, were associated with reductions in the hazard ratio for CVD mortality of 0.42 and 0.29 (p for trend < 0.001) respectively compared to individuals with low activity levels. (This was after adjusting for age, area, study year, and sex.) For incident CVD events, the comparable adjusted hazard ratios were 0.65 and 0.50 (< 0.001), respectively, for an incident CVD event. Benefit changed but only modestly after even further adjusting for smoking, body mass index, systolic blood pressure, serum total cholesterol, education and marital status.
So, Jousilahti et al. concluded that physical activity is associated with a reduced risk of CVD mortality and incident CVD events, even in older adults independently of the major known CVD risk factors. The protective effect of physical activity was dose dependent, with a higher level of physical activity showing a stronger association.
Machine-learning Score Bests CHA2DS2-VASc
Identifying atrial fibrillation (AF) patients who are truly “low risk” is an ongoing challenge, but a new machine learning-derived risk score appears to do a much better job of it than any of the currently available published scores, according to findings presented by Keith A. A. Fox, MBChB (University of Edinburgh, UK).
Based on real-world data from the global GARFIELD-AF registry it appears that while the use of anticoagulation is rising, it’s not being used properly. Full 51% of very low risk patients, meaning a CHA2DS2-VASc of zero, are anticoagulated, while 28% of high-risk patients (CHA2DS2-VASc ≥2) are not being anticoagulated.
“This suggests to us that there are factors beyond the current risk scores that actually determine the choice of anticoagulation or not,” said Professor Fox. “Our hypothesis was that if we provide a more accurate and user-friendly risk score, maybe we will have more rational and guideline-based performance.”
The researchers employed a technique called coalescent regression, which avoids the need to specify levels of relatedness in the statistical model and allows joint modeling of all outcomes. Machine learning involves using computers to do the figuring and skipping the basic regression analysis used in most risk prediction models. Rather than relying on a pre-specified theory or set of assumptions, the machine models can search for the optimal fit within certain constraints (specific to the individual algorithm). (You can read more about risk scores in our CSWN September 2016 cover story.)
The GARFIELD-AF Score is based on the analyses of data from 38,984 patients enrolled in the registry between March 2010 and July 2015. The model was designed to predict—for the first time in one score—the outcomes of mortality, ischemic stroke/systemic embolism, and hemorrhagic stroke/major bleeding.
The researchers developed a full model designed to reside in the electronic health record and to automatically extract the information needed to calculate the score, said Dr. Fox, but they also developed a simplified model to be used as a web or mobile application. The performance of both models were compared with the CHA2DS2-VASc risk score.
Overall, the GARFIELD score offered superior discriminatory value in predicting the outcomes of all-cause mortality, ischemic stroke/systemic embolism or hemorrhagic stroke/major bleeding (Table 1).
Looking just at low-risk patients (CHA2DS2-VASc 0 or 1 in men and 1 or 2 in women), the differences were even more apparent (Table 2). Keep in mind, a C statistic of 0.50 indicates that the model predicts no better than flipping a coin, while a model that yields a C statistic >0.8 is considered strongly predictive (Table 2).
External validation was undertaken using an independent contemporary registry (ORBIT-AF). The new score fared well despite the endpoints being slightly different.
“The more comprehensive GARFIELD Score includes multiple variables, beyond that of CHA2DS2-VASc, and this increased granularity will help to optimize the management of low-risk patients,” said Professor Fox in a press release. Renal function, in particular, is included in GARFIELD, but not in CHA2DS2-VASc. – Heart
Limit Anticoagulation After Unprovoked VTE?
A clinical decision rule (CDR) can suggest which women can discontinue anticoagulants after unprovoked venous thromboembolism (VTE). According to Marc Rodger, MD (Ottawa Hospital and University of Ottawa, Ontario, Canada), “Since current consensus guidelines suggest anticoagulants should be continued indefinitely in all patients with unprovoked VTE and non-high bleeding risk, our results are potentially practice-changing.”
He and his colleagues prospectively validated the HERDOO2 rule in the REVERSE II trial of 622 patients with a first, unprovoked VTE who were considered low-risk, based on HERDOO2 criteria and the majority of these discontinued anticoagulant therapy.
The HERDOO2 rule is named for the 4 risk factors that must be considered in determining a patient’s risk of VTE recurrence:
- Hyperpigmentation, edema or redness in either leg;
- D-dimer > 250 μg/ml on anticoagulants;
- Obesity with body mass index (BMI) > 30 kg/m2;
- Older than age 65.
The investigators said this would make HERDOO2 the only currently validated CDR to assist clinicians, patients, and policy makers in deciding who can discontinue anticoagulants after unprovoked VTE. Said Dr. Rodger, “This is an important finding as, using our rule, over half of women with unprovoked VTE (meaning VTE with no precipitant), can safely discontinue anticoagulants and be spared the burdens, costs, and risks of lifelong anticoagulation.” In brief, he added, ““If your 1-year risk of recurrent VTE off blood thinners is 5%, then you will not benefit from being on anticoagulants.”
Apheresis or Alirocumab
A small study suggests that most patients with heterozygous familial hypercholesterolemia (HeFH) might be able to replace apheresis treatments with the PCSK9 inhibitor alirocumab.
Sixty-two patients with HeFH undergoing apheresis whether weekly or every 2 weeks were randomized to either alirocumab 150 mg (n = 41) or placebo (n = 21) every 2 weeks for 18 weeks while continuing their regular lipid-lowering medications. For the first 6 weeks, apheresis was continued according to the patient’s schedule, but was then adjusted for weeks 7 through 18 based on individual needs. If a patient’s LDL-C had dropped by 30% or more since the start of the study, apheresis was skipped.
At the end of the study, the PCSK9-treated patients had a 75% greater reduction in apheresis compared to those on placebo (p < 0.0001). In fact, 63.4% of patients on alirocumab eliminated apheresis altogether (compared to none in the placebo group) and 92.7% avoided at least half of the procedures (compared to 14.3% in the placebo arm).
The study’s lead investigator, Patrick M. Moriarty, MD (University of Kansas Medical Center, in Kansas City) said, ““In the future, lipoprotein-apheresis centers may now add alirocumab to a patient’s lipid-lowering therapy and possibly not have to treat them with apheresis or at least treat them less often. Since the drug has already been approved for this patient population (HeFH and high CVD risk) it can be now considered part of standard care for these patients intolerant to other LLT.” – European Heart Journal
STEMI Presentation During Off-hours
Is it really more hazardous to present with an ST-elevation MI during “off-hours” than “on hours?” Maybe not anymore.
Previous data have suggested worse outcomes for patients presenting with STEMI during off-hours compared with during the normal workday. It makes sense given changes in staffing, delays in intervention, and higher procedural complications. Yet, available data derive from registries with retrospective collection of clinical characteristics and outcomes, with little available evidence from prospective, randomized trials.
Therefore, the CHAMPION-PHOENIX investigators analyzed their data to determine the impact of time at presentation on outcomes. The study proper evaluated the effect of platelet inhibition with cangrelor during PCI on subsequent ischemic events. In the STEMI cohort of CHAMPION PHOENIX (1,992/10,942), with off-hour PCI defined as an intervention performed during weekdays from 7PM to 7AM, weekends, or holidays.
The primary efficacy outcome was a combined endpoint of all-cause death, MI, stent thrombosis, or ischemia-driven revascularization at 48 hours. The primary safety outcome was bleeding at 48 hours.
The risk of the primary efficacy outcome was not significantly different for on-hours presentation, whether based on unadjusted analysis (p = 0.67) or after multivariate adjustment (Table 3). There was no significant difference in risk of stent thrombosis (ST) with on-hours PCI or in the primary safety outcome. Additionally, no interaction was observed by site of enrollment (p >0.05 for all outcomes).
Granted, this was not a pre-specified analysis of CHAMPION PHOENIX; nevertheless, it's reassuring that, in contrast to findings from several prior studies, time of PCI did not affect STEMI efficacy or safety outcomes. The data suggest that outcomes for STEMI revascularization are not dependent upon time of presentation. -Journal of the American College of Cardiology
- Bittl JA, Baber U, Bradley SM, Wijeysundera DN. J Am Coll Cardiol. 2016;68:116-39
- Levine GN, Bates ER, Bittl JA, et al. J Am Coll Cardiol. 2016;68:1082-115.
In Conclusion, No
Several anticipated studies at ESC turned out to be negative trials, but in a couple cases there may be a bright spot for additional research.
Monitoring platelet function in order to individualize antiplatelet therapy did not improve outcomes for elderly patients after an MI versus a standard, unmonitored approach. Gilles Montalescot, MD, PhD. Hopital Pitie-Salpetriere, Paris, France: “Platelet function testing is still being used in many centers to measure the effect of antiplatelet drugs, but our study does not support this practice.” (Lancet)
Survival and other cardiovascular outcomes were not significantly reduced when combining a second-line cholesterol-lowering medication (ezetimibe) on top of a standard statin (pitavastatin) compared to statin treatment alone in patients with acute coronary syndrome and dyslipidemia. Nobuhisa Hagiwara, MD, PhD, Tokyo Women’s Medical University, Tokyo, Japan: “Intensive LDL lowering with a statin and ezetimibe did not significantly reduce cardiovascular events more than a statin alone in ACS patients, but the combination did reduce events more than a statin alone in patients with higher baseline levels of sitosterol, a cholesterol absorption marker.”
Enhanced cardiac rehabilitation programs that include a year of group or personal lifestyle and fitness coaching did not improve cardiovascular risk scores more than a standard 3-month program in patients recovering from myocardial infarction. Ron van Domburg, PhD, Erasmus Medical Center Rotterdam, the Netherlands: “Although we were not able to show any greater improvement in metabolic parameters such as cholesterol, blood pressure, BMI, or waist circumference associated with the enhanced protocol overall, there were some initial indications that a firm commitment to a year-long program might encourage more permanent lifestyle improvements.”
More than 3 years of nightly treatment with a continuous positive airway pressure (CPAP) machine did not reduce cardiovascular risk more than usual care among patients with cardiovascular disease and obstructive sleep apnea. Doug McEvoy, MD, Flinders University, Adelaide, Australia: “Given the level of risk of cardiovascular disease attributed to obstructive sleep apnea, we were surprised not to find a benefit from CPAP treatment.” One bright spot: “In contrast to its neutral effects on cardiovascular endpoints, CPAP significantly improved patient well-being: patients experienced less snoring, less daytime sleepiness, had less depression and overall, there was an improvement in quality of life.” (NEJM)
REM-HF and MORE-CARE
Supporters of remote monitoring (REM) may not be ‘losing their religion’ quite yet, but their faith is being tested. Findings from the Remote Management of Heart Failure Using Implantable Electronic Devices trial (REM-HF, Royal Brompton Hospital, London, UK) showed that REM was not associated with reduced mortality or fewer cardiovascular hospitalizations compared to usual care. For REM, ‘It’s not the end of the world as we know it,’ but the MOnitoring Resynchronization dEvices and CARdiac patiEnts trial (Modena, Italy) showed no benefit on hard clinical endpoints after recruiting just over 900 HF patients implanted with a CRT-defibrillator with wireless transmission capabilities. One bonus: the investigators reported cost savings due to a 41% reduction of in-office visits. – JAMA (REM-HF) and European Journal of Heart Failure (MORE-CARE)
The Congestive Heart Failure Cardiopoietic Regenerative Therapy trial evaluated bone-marrow stem cells to promote heart repair, but this approach did not significantly improve the primary outcome over a sham procedure among patients with congestive HF. However, CHART-1 revealed what the investigators called critical new insights, identifying a "well-defined" subgroup of patients who may benefit from cardiopoietic cell therapy: those with severe heart enlargement at baseline (left ventricular end-diastolic volumes between 200 and 370 ml).
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