With no firm answers, conversation should guide therapy
Cover Story | By Rick McGuire
Conversely, sometimes guideline authors review the data, don’t find enough that qualifies as “evidence-based,” or the data suggest a number of reasonable options; so, guidelines are opting for more “shared decision-making” between physician and patient or, at other times, a requirement for “team-based care.” This covers the basics (statin therapy) as well as interventional cardiology (PCI? CABG? Medical therapy?).
Reviewing the 2015 meeting of the European Society of Cardiology in London, UK, there are more cases wherein data give no clear answer, but certainly suggest options—ones that should be discussed with the patient.
Extended DAPT: Yes, No, or Maybe
The authors of the OPTIDUAL trial suggest that extending dual antiplatelet therapy (DAPT) beyond the recommended 12 months after coronary stenting “should be considered” in patients at low risk for bleeding. In reporting the results, news reports on the trial ranged from “Results Suggest Extending Post-stenting DAPT Beyond 1 Year” to “No Clear Need to Lengthen DAPT” to “No Harm, No Foul with DAPT after 4 Years.”
Not exactly black and white.
Here’s what the OPTIDUAL trial showed: In 1,385 patients from 58 French sites, a combination of aspirin and clopidogrel did not decrease the rate of major adverse cardiovascular and cerebrovascular events (MACCE, see FIGURE 1), but there was “a hint” it might reduce ischemic outcomes without excess bleeding. Specifically, the results showed a borderline reduction in ischemic outcomes (a post-hoc outcome composite rate of death, myocardial infarction [MI], or stroke) with extended DAPT (4.2% in the extended-DAPT group and 6.4% in the aspirin group; hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.40–1.02; p=0.06) without increased bleeding (2.0% in both groups) or increased all-cause mortality.
According to principal investigator Gérard Helft, MD, PhD, from the Institut de Cardiologie, Hôpital Pitié-Salpétrière, in Paris, France, “Given the lack of harm and the signal for benefit of prolonged DAPT in the OPTIDUAL trial, and the results from prior randomized trials testing long durations of DAPT, prolongation of DAPT beyond 12 months should be considered in patients without high-risk bleeding, who have received a drug-eluting coronary stent and are event-free at 12 months.”
In a press conference, Dr. Helft acknowledged that determining the optimal approach for any given patient is “difficult.” Better risk stratification is certainly needed. That means more use of CHA2DS2-VASc score (which calculates stroke risk for patients with atrial fibrillation [AF]) and the bleeding risk score known as HAS-BLED.
Marco Roffi, MD, FACC, a professor at University Hospital of Geneva, Switzerland, noted during the live “Best of ESC” program broadcast soon after the meeting that, while OPTIDUAL was underpowered, the intimation of benefit goes in the same direction as a meta-analysis presented at the meeting; this suggests that prolonged DAPT was associated with a 22% relative risk reduction in MACCE, corresponding to an absolute 1.1% risk reduction in events and a number needed to treat of 90. “This has to be weighed against the increased risk of major bleeding in the same meta-analysis,” said Dr. Roffi. “So, I think, the guidelines are correct and you have to assess risk of ischemic events and risk of bleeding and then decide on a case-by-case fashion. But for the first time, the (new ESC) guidelines open the way for prolonged dual antiplatelet therapy in patients at high ischemic risk and low bleeding risk.”
Specifically, while the general recommendation of DAPT for 1 year remains, the new ESC guidelines for managing those patients with acute coronary syndrome (ACS)—who require percutaneous coronary intervention (PCI)—state that a tailored duration (i.e., shortened to 3-6 months or extended up to 30 months) is now allowed in selected patients at high-bleeding or high-ischemic risk, respectively.1 Professor Roffi acknowledged that balancing risk with benefit is “not easy.” He stressed, “If you have a patient with acute myocardial infarction undergoing stenting then reassess the patient at 12 months. At this time, use the criteria of the PEGASUS study, which determined risk based on the presence of diabetes, multivessel disease, renal insufficiency—maybe the patient has already had multiple events; if they have such risk factors, then maybe consider prolonged (DAPT) if they remained free of bleeding events.”
Catheter Ablation: First-line Rx for AF?
Currently, antiarrhythmic drug (AAD) therapy is considered first-line treatment for symptomatic AF, and catheter ablation is used for patients who fail drug therapy. Maybe catheter ablation should be considered for initial therapy, too.
MANTRA-PAF (Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation) was an international study and the first to test ablation versus AAD therapy in AAD-naïve paroxysmal AF patients.2 Early on, the two approaches were equally efficacious but, over time, ablation was shown to be more effective than drug therapy. Specifically, at 3, 6, 12, and 18 months, there was no significant difference in the amount of time patients in the two groups experienced AF (called AF burden). Nor was there any difference in cumulative AF burden. However, at 24 months, the catheter ablation group had significantly less AF burden than the drug-treated patients. Moreover, patients in the intervention arm reported a higher quality of life at 12 and 24 months compared to those patients assigned to drug therapy.
The 5-year outcomes of MANTRA-PAF were presented at ESC, and data was available for 245 out of 294 patients (83%), of whom 125 had been randomized to catheter ablation and 120 to AAD therapy as first-line treatment. Holter recording was available for 227 patients. More patients in the catheter ablation group were free from any AF (126/146 vs. 105/148; p = 0.001) and symptomatic AF (137/146 vs. 126/148; p = 0.015) than those in the AAD therapy group. Atrial fibrillation burden was significantly lower in the catheter ablation group (any AF: p = 0.003; symptomatic AF: p = 0.02) compared to AAD therapy.
Professor Jens Cosedis Nielsen, MD, consultant cardiologist at Aarhus University Hospital in Denmark, presented the data. Like they did when the initial 2-year results were presented, the authors emphasized that while catheter ablation appears to be an option for previously untreated patients with paroxysmal AF, it should be up to the clinician to weigh the benefits and risks. Importantly, the MANTRA-PAF investigators emphasized that the results are not an argument for offering all patients with paroxysmal AF radiofrequency ablation. Both strategies should be discussed with patients and considered by patients and physicians when rhythm control for symptomatic paroxysmal AF is indicated.
William Stevenson, MD, FACC, of Harvard’s Brigham and Women’s Hospital, Boston, MA, was the discussant for the 2-year MANTRA-PAF results and his comments remain applicable. The director of the clinical cardiac electrophysiology program at Brigham noted that ablation for periodic AF carries benefits and risks. The efficacy with catheter ablation is better than drug therapy and offers freedom from drug toxicities. On the other hand, like any procedure, there are complications associated with ablation. Also, AF commonly recurs early, so patients may require more than one ablation procedure.
Here again: talk to the patient. Hugh Calkins, MD, director of the cardiac arrhythmia service at Johns Hopkins, Baltimore, MD, added in a recent editorial: “Catheter ablation of AF should not be considered a ‘curative procedure’ for most patients with AF [and] it is not a risk-free procedure. Patient preference and operator experience are important. In clinical practice, it is uncommon to find a patient who is eager to undergo catheter ablation without at least one trial of anti-arrhythmic medication.”3 This is especially true, he said, after a thorough discussion of the risks of the procedure and the fact that 30% to 50% of patients require a repeat procedure.
Pretreatment Paradigm Shift
The guidelines task force members felt that the most controversial area they addressed was the optimal time to give P2Y12 inhibitors to non-ST-elevation ACS patients scheduled for invasive assessment. The 2011 ESC Guidelines recommended the antiplatelet agent be given as soon as a diagnosis was made, independently of when the patient would undergo coronary angiography. The first study designed to test the impact of P2Y12 inhibitor pretreatment in ACS showed that early prasugrel resulted in more bleeding events compared to giving the drug at the time of coronary angiography/PCI and with no counterbalancing of fewer ischemic events.
Professor Carlo Patrono, MD, task force co-chair and chair of the Department of Pharmacology at the Catholic University School of Medicine, Rome, Italy, said, “Prasugrel pretreatment is now contraindicated, which is a change of paradigm. In retrospect, we were over confident about the value of P2Y12 inhibitor pretreatment.” What about other options? This time the problem is a lack of evidence-based data. Dr. Patrono added, “With respect to ticagrelor and clopidogrel, the optimal timing of drug administration in patients scheduled for an invasive strategy has not been properly studied, so we do not give any recommendation for or against pretreatment. This is a gap in evidence that requires further research.”
Studies presented at ESC tried to get at the timing issue. The original ATLANTIC study, a late-breaker from ESC.14, was a randomized, multinational, double-blind, placebo-controlled trial in which 1,862 patients with ST-elevation MI were randomized to either pre- or in-hospital ticagrelor at an 180 mg loading dose. In London at ESC.15, conference goers heard about ATLANTIC-H24, a landmark exploratory analysis in 1,629 patients who underwent primary PCI in the ATLANTIC trial.
At 24 hours, the composite ischemic endpoint of death, MI, stent thrombosis, stroke, or urgent revascularization was reduced with pre-hospital ticagrelor (10.4% vs. 13.7%; p = 0.0389), as were individual endpoints of definite stent thrombosis (p = 0.0078) and MI (p = 0.0311). All endpoints except death (1.1% vs. 0.2%; p = 0.0477) favored pre-hospital ticagrelor. There were no differences in bleeding events.
According to Gilles Montalescot, MD, head of the Cardiology Department at Pitié-Salpétrière Hospital, Paris, France, “This is an important finding because ticagrelor is needed in primary PCI but an earlier time of administration (before hospitalization) may have an impact on the prevention of ischemic events occurring during the first 24 hours following the procedure.”
“We hypothesized that pre-hospital ticagrelor may not have improved coronary reperfusion before PCI because of the short average transfer time of 31 minutes and that the effects might occur after PCI,” said Dr. Montalescot, the principal investigator of the study.
He added, “We found differences in platelet reactivity and immediate post-PCI reperfusion that were associated with reductions in ischemic endpoints. This confirms that clinicians should consider giving ticagrelor to patients on their way to hospital for primary PCI to improve outcomes after the procedure.”
Rapid Rule-In, Rule-Out
When it comes to chest pain, people want to know whether it’s that pizza they ate just before bed or whether their ticker needs testing; if they get any tests they want an answer—now! And let’s face it: the stress of sitting around a crowded ER wondering whether you are having a heart attack or not is not particularly amenable to heart health. Here is one area where the data are less equivocal.
For patients presenting with symptoms of myocardial infarction, the current standard is analyzing cardiac troponin I (TnI) directly at admission and then 3 hours later (0 hr/3 hr), to determine if the level warrants admission or discharge. The BACC (Biomarkers in Acute Cardiovascular Care) study included 1,045 patients (mean age 65 years) with acute chest pain suggestive of acute MI (AMI) presenting at the emergency room of the University Hospital in Eppendorf, Hamburg, Germany.
Patients were assessed using both the standard 3-hour assay as well as a highly-sensitive 1-hour assay (in other words, TnI measured at 0 h/3 h or 0 h/1 h). Ruling out NSTEMI with hsTnI ≤6 ng/l resulted in 402 patients being discharged by 1 hour. All patients were then followed for 6 months. The investigators calculated the best TnI cut-off value to rule out AMI as 6 ng/l.
Principal investigator, Dirk Westermann, MD, PhD, of the University Heart Centre Hamburg, Germany, reported that he and his colleagues then applied the new cut-offs to the BAAC cohort and found that mortality would have been lower if patients had been triaged with the new algorithm compared to the routine 3-hour approach.
“The standard approach underestimated risk for many patients and resulted in high mortality,” said Dr. Westermann. Frankly, he said, they would have missed patients with MI and would have discharged them had they used the 99th percentile cutoff of 27 ng/l contained in the current guidelines. (Well, the current guidelines at the time the study was conducted.) Janina Stępińska, MD, PhD, of the Cardinal Stefan Wyszyński Institute of Cardiology in Poland, agreed: “Looking at the overcrowded emergency rooms the world over, this is an important result. You can discharge 50% of these patients safely.”
The study was really a three-parter: calculate the best performing cut-off and apply it; validate the results in other cohorts; and apply the cut-off to a general population. As for part two, Dr. Westermann noted that the algorithm has been validated in two independent cohorts (ADAPT and APACE trials) that included 4,009 patients with acute chest pain suggestive of AMI.
The final act was to test the clinical relevance of this new cut-off for predicting cardiovascular events using data from the BiomarCaRE study—one of the largest studies to include TnI measurement in more than 75,000 individuals from the general population. The data confirmed that individuals from the general population with troponin I values >6 ng/l were at increased risk of death or cardiovascular disease, whereas patients with levels of <6 ng/l could be safely discharged home.
As released at the meeting in London, the ESC guidelines now offer two options: for patients presenting with possible AMI, clinicians can use either the standard 0 h/3 h algorithm or, as an alternative, 0 h/1 h assessments are recommended when high-sensitivity cardiac troponin assays with a validated algorithm are available. The guidelines do not offer a cutoff, but do note that “additional testing after 3-6 h is indicated if the first two troponin measurements are not conclusive and the clinical condition is still suggestive of ACS.”
A PLATFORM for FFRCT
Once you know whether it’s ACS or not, the next step is what to do about it. In an effort to further speed the process along, two recent trials (PROMISE and SCOT-HEART) compared anatomic and functional strategies, finding that coronary computed tomographic angiography (CCTA) improved processes of care for coronary artery disease (CAD). However, CCTA also increased rates of invasive catheterization and revascularization with no significant reduction in events.
At ESC.15, Pamela S. Douglas, MD, MACC, who was first author of PROMISE,4 presented the results of a study evaluating fractional flow reserve-derived from CCTA, an approach that might address these limitations by providing both functional and anatomic data.
PLATFORM (Prospective LongitudinAl Trial of FFRCT: Outcome and Resource IMpacts) enrolled a symptomatic, intermediate-risk population for whom testing is currently recommended. Patients with chest pain underwent CCTA scanning: 287 had an immediate stress test or catheterization to determine whether a blocked artery caused their symptoms and 297 patients were sent for CCTA followed by fractional flow reserve analysis by CT, or FFRCT. Use of CT/FFRCT in patients with planned invasive catheterization was associated with a reduction in the rate of finding no obstructive CAD at invasive coronary angiography (ICA), from 73% (in a parallel group undergoing standard assessment) to 12% (FIGURE 2). Similar results were seen in all subgroups and there was no differences in major adverse cardiac events, radiation, or revascularization rates.
Bottom line: Dr. Douglas, who is the Ursula Geller Professor at the Duke Clinical Research Institute, Durham, NC, said, “This approach significantly reduced the need for unnecessary invasive coronary angiography (61% of ICAs were cancelled) which, although it is the gold standard for investigating chest pain, comes with the risk and costs of an invasive procedure.”
She added, “There is a powerful message here: If you are planning to undergo a cardiac catheterization, you should consider a CTA scan with FFRCT first. This is the kind of information physicians should seek and patients should be armed with to avoid a potentially unnecessary, invasive procedure.”
We mentioned the new ESC guidelines relating to managing patients with ACS.1 One of the biggest changes: There is now a class I A indication for radial PCI in the setting of acute MI. As Dr. Roffi put it (he chaired the ESC task force that developed the new guidelines), “Go radial!” He added that the recommendation urging use of radial access was included “because it not only reduces vascular and bleeding complications but also mortality. So, we are now encouraging all centers who manage patients with acute MI to switch from femoral to radial.”
Having said that, he noted, “Proficiency in the femoral approach should be maintained, as this access is indispensable in a variety of procedures, including intra-aortic balloon counterpulsation implantation, structural heart disease interventions, and peripheral revascularization procedures.”
Leadless or Needless?
We’re half a century into cardiac pacing technology and transvenous leads remain the weakest link. This fact led investigators more than 40 years ago to consider the possibility of leadless cardiac pacing.5 The devices under development today are winning awards for innovation, as we noted last month in our cover story on miniaturization in cardiovascular medicine. At the 2015 European Heart Rhythm Association (EHRA) meeting, Medtronic’s Micra™ Transcatheter Pacing System (TPS) won the top innovation award for practice improvement as did St. Jude’s leadless pacing device, Nanostim™, just the year before at EHRA’s CARDIOSTIM2014.
Nevertheless, leadless pacing has had a rough year. St. Jude’s device obtained a CE mark in 2013, but sales were temporarily halted last year when a post-marketing study in Europe of about 200 patients revealed two patient deaths and six instances of perforation. The trial re-started in the summer of 2014, only to be halted again in January 2015. (The Nanonstim remains investigational in the United States, whereas the Micra TPS is investigational in both Europe and the United States.) The early results of the Micra TPS Study were recently reported. The device was successfully implanted in all patients (n = 140) but 26 patients (18.6%) experienced either a protocol-defined procedure or system-related adverse event, including four patients with transient atrioventricular block, two with ventricular tachycardia, one with ventricular fibrillation, and one with pericardial effusion without tamponade.
At ESC.15, results for the Nanostim LEADLESS II trial were presented and published simultaneously.6 According to the principal investigator, Vivek Reddy, MD, of the Icahn School of Medicine at Mount Sinai in New York City, NY:
- The device was successfully implanted in 96% of patients attempted.
- There is about a 6.7% rate of major complications (among the 300 patients followed for at least 6 months) “that we expect to decrease over time.” Why? “Remember,” said Dr. Reddy, “99% of operators had never performed this device implantation before.”
- The vast majority of successfully implanted patients have adequate sensing and pacing over the long term.
- The expected longevity of this device is out to 15+ years.
Cecilia Linde, MD, head of cardiology at the Karolinska Institute Stockholm, Sweden, said she thinks the complications were often related to the 18 F sheath used to implant the leadless pacemaker. Also, she added, the place for single-chamber pacing is quite limited, with maybe about 10% of patients requiring pacing.
The major adverse events included device dislodgement requiring percutaneous retrieval (in 1.7%), cardiac perforation (1.3%), and pacing-threshold elevation requiring retrieval and device replacement (1.3%).
According to Keith A. A. Fox, MD, FACC, professor of cardiology at the University of Edinburgh, Scotland, leadless pacing is “on its way, but it’s not there yet.”
Not Exactly a CIRCUS for Myocardial Reperfusion Injury
Here’s something you won’t have to worry about discussing with your patients any time soon. There has been substantial experimental evidence to suggest that cyclosporine can reduce infarct size and improve cardiac function, but when the phase III study known as CIRCUS (Does Cyclosporine ImpRove Clinical oUtcome in ST-elevation myocardial infarction patients) tried juggling cyclosporine versus placebo, all those balls fell to the ground.
The study included patients with anterior STEMI undergoing PCI within 12 hours of symptom onset and with complete occlusion of the culprit coronary artery. Patients were randomly assigned to receive a 2.5 mg/kg intravenous bolus injection of cyclosporine (n = 395) or matching placebo (n = 396) before coronary recanalization. The rate of the primary outcome (composite of any-cause death, worsening of heart failure during initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year) was 59.0% in the cyclosporine group versus 58.1% in the control group (p = 0.77). Cyclosporine also did not reduce the incidence of separate clinical components of the primary outcome or other events including recurrent infarction, unstable angina, or stroke (Table).7
“We were very surprised and disappointed,” according to lead investigator Michel Ovize, MD, PhD, from Claude Bernard University, Lyon, France. “There is substantial experimental evidence that cyclosporine can reduce infarct size and improve cardiac function, and we previously published a small-size phase II trial suggesting that cyclosporine may reduce infarct size in STEMI patients.8 Obviously, the larger phase III CIRCUS study did not confirm this, and the reason for this discrepancy in unclear.”
In an accompanying commentary to the published CIRCUS results,9 Derek J Hausenloy, MB, CHB, PhD, FACC, and Derek M. Yellon, DSc, FACC, wrote, “Although the results of the CIRCUS study are disappointing, they do not disprove the existence or clinical significance of myocardial reperfusion injury, because it appears the formulation of cyclosporine used in the study might not have been effective at preventing myocardial reperfusion injury.”
- Roffi M, Patrono C, Collet JP, et al. Eur Heart J. 2015 Aug 29. [Epub ahead of print].
- Nielsen JC, Johannessen A, Raatikainen P, et al. N Engl J Med. 2012;367:1587-95.
- Calkins H. JAMA. 2014;311:679-80.
- Douglas PS, Hoffmann U, Patel MR, et al. N Engl J Med. 2015;372:1291-300.
- Lown B, Kosowsky BD. N Engl J Med. 1970;283:907-16.
- Reddy VY, Exner DV, Cantillon DJ, et al. N Engl J Med. 2015 Aug 30. [Epub ahead of print].
- Cung TT, Morel O, Cayla G, et al. N Engl J Med. 2015; 373:1021-31.
- Piot C, Croisille P, Staat P, et al. N Engl J Med. 2008; 359:473-81.
- Hausenloy DJ, Yellon DM. N Engl J Med. 2015;373:1073-5.
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