Anatomical vs. Functional Testing PROMISE trial data reveal outcomes, economic costs of evaluating patients with suspected CAD Positive TAVR Outcomes in PARTNER 1 System rivals surgery in high-risk operable patients, surpasses standard care in inoperable patients Long-Term Dual Antiplatelet Therapy After MI Ticagrelor plus aspirin beyond 1 year bodes well for patients with low bleeding risk in PEGASUS–TIMI 54 Third-Generation Valve Replacements SAPIEN 3 TAVR system reduces death, stroke in patients at high risk for surgery PCSK9 Inhibitor Defends Against CV Events OSLER studies show safety, efficacy of evolocumab to reduce LDL and potential increase in heart benefits The Watchman in Practice FDA-approved left atrial appendage closure device adds to nonvalvular atrial fibrillation treatment options This CARDIOLOGY TODAY supplement is produced by SLACK Incorporated. JUNE 2015 PERSPECTIVES FROM ACC Scientific Sessions A CARDIOLOGY T ODAY Special Report Supplement to
Transcript
Supplement to
Anatomical vs. Functional TestingPROMISE trial data reveal outcomes, economic costs of evaluating patients with suspected CAD
Positive TAVR Outcomes in PARTNER 1System rivals surgery in high-risk operable patients, surpasses standard care in inoperable patients
Long-Term Dual Antiplatelet Therapy After MITicagrelor plus aspirin beyond 1 year bodes well for patients with low bleeding risk in PEGASUS–TIMI 54
Third-Generation Valve ReplacementsSAPIEN 3 TAVR system reduces death, stroke in patients at high risk for surgery
PCSK9 Inhibitor Defends Against CV EventsOSLER studies show safety, efficacy of evolocumab to reduce LDL and potential increase in heart benefits
The Watchman in PracticeFDA-approved left atrial appendage closure device adds to nonvalvular atrial fibrillation treatment options
This Cardiology Today supplement is produced by SLACK Incorporated.
JUNE 2015
PERSPECTIVES FROM ACC Scientific SessionsA Cardiology Today Special Report
Supplement to
2 | MAY 2015 | Healio.com/CT
T he American College of Cardiology’s 64th Annual Scientific Sessions showcased a broad range of ab-stracts from a community of researchers dedicated to making discoveries that will enhance treatment, empower clinicians and improve patient care.
Steeped in the theme “more learning and less lecturing,” the sessions presented over 3 days in San Diego, Calif., highlighted challenges the cardiology community currently faces as well as areas of opportunity.
Meeting organizers lauded the recent advances in transcatheter therapies, improvements in monitoring HF and ACS, and growing understanding of genetics — all presenting potential targets for continued clinical investigation.
This Cardiology Today supplement provides a glimpse of the groundbreaking — and sometimes game-changing — findings from the PROMISE, PARTNER 1, PEGAGUS-TIMI 54, PARTNER II S3 and OSLER trials presented at the conference, with perspectives from Cardiology Today editorial board members and other leading experts. Their opinions and experience in the field will broaden the context to what it means for everyday practice and the future. n
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8.6 Renal Impairment Renal clearance accounts for approximately 50% of the total clearance of edoxaban. Consequently, edoxaban blood levels are increased in patients with poor renal function compared to those with higher renal func-tion. Reduce SAVAYSA dose to 30 mg once daily in patients with CrCL 15-50 mL/min. There are limited clinical data with SAVAYSA in patientswith CrCL < 15 mL/min; SAVAYSA is therefore not recommended in thesepatients. Hemodialysis does not significantly contribute to SAVAYSA clear-ance [see Dosage and Administration (2.1, 2.2) and Clinical Pharmacology(12.3) in the full prescribing information]. As renal function improves and edoxaban blood levels decrease, the risk forischemic stroke increases in patients with NVAF [see Indications and Usage(1.1), Dosage and Administration (2.1), and Clinical Studies (14.1) in thefull prescribing information]. 8.7 Hepatic ImpairmentThe use of SAVAYSA in patients with moderate or severe hepatic impair-ment (Child-Pugh B and C) is not recommended as these patients may haveintrinsic coagulation abnormalities. No dose reduction is required inpatients with mild hepatic impairment (Child-Pugh A) [see Clinical Pharma-cology (12.3) in the full prescribing information].8.8 Low Body Weight Consideration for Patients treated for DVT and/or PEBased on the clinical experience from the Hokusai VTE study, reduceSAVAYSA dose to 30 mg in patients with body weight less than or equal to60 kg [see Dosage and Administration (2.2) and Clinical Studies (14.2) inthe full prescribing information].
10 OVERDOSAGEA specific reversal agent for edoxaban is not available. Overdose ofSAVAYSA increases the risk of bleeding.The following are not expected to reverse the anticoagulant effects of edoxaban: protamine sulfate, vitamin K, and tranexamic acid.Hemodialysis does not significantly contribute to edoxaban clearance [seePharmacokinetics (12.3) in the full prescribing information].
17 PATIENT COUNSELING INFORMATIONAdvise the patient to read the FDA-approved patient labeling (MedicationGuide).Advise patients of the following:• they may bleed more easily, may bleed longer, or bruise more easily
when treated with SAVAYSA
• to report any unusual bleeding immediately to their healthcare provider• to take SAVAYSA exactly as prescribed• to not discontinue SAVAYSA without talking to the healthcare provider
who prescribed it• to inform their healthcare providers that they are taking SAVAYSA before
any surgery, medical, or dental procedure is scheduled• to inform their healthcare providers and dentists if they plan to take, or
are taking any prescription medications, over-the-counter drugs or herbalproducts
• to inform their healthcare provider immediately if they become pregnantor intend to become pregnant or are breastfeeding or intend to breastfeedduring treatment with SAVAYSA
• that if a dose is missed, take SAVAYSA as soon as possible the same day,and resume the normal dosing schedule the following day. The doseshould not be doubled to make up for a missing dose
• that if they are having neuraxial anesthesia or spinal puncture, advisepatients to watch for signs and symptoms of spinal or epidural hematoma,such as back pain, tingling, numbness (especially in the lower limbs),muscle weakness, and stool or urine incontinence. If any of these symp-toms occur, advise the patient to contact his or her physician immediately[see Boxed Warning].
I n symptomatic patients with suspected CAD requiring noninvasive testing, initial CTA and functional testing were
associated with no difference in outcomes at 2 years, according to the results of the PROMISE trial.
Also presented at the American Col-lege of Cardiology Scientific Sessions, an economic analysis of PROMISE indicated similar costs of both strategies in the same patient population over 3 years.
Pamela S. Douglas, MD, and col-leagues randomly assigned 10,003 symptom-atic patients (mean age, 60.8 years; 52.7% women; 87.7% with chest pain or dyspnea upon exertion) to initial anatomical testing with coronary CTA or with functional test-ing, defined as exercise electrocardiography, nuclear stress testing or stress echocardiog-raphy. Mean pretest likelihood of obstructive CAD was 53.3%.
The composite primary endpoint was death, MI, hospitalization for unstable an-
gina or major procedural difficulties. Sec-ondary endpoints included invasive cardiac catheterization not showing CAD and ra-diation exposure. Median follow-up was 25 months.
During the study period, the primary endpoint occurred in 3.3% of patients in the CTA group vs. 3% of those in the functional testing group (adjusted HR = 1.04; 95% CI, 0.83-1.29).
“It is a very significant finding that there was a very low event rate in our patients,” Douglas said.
Compared with functional testing, CTA was associated with fewer catheterizations showing no obstructive CAD (3.4% vs. 4.3%; P = .02), although more people in the CTA group (12.2%) underwent catheter-
ization within 90 days of randomization than those patients in the functional testing group (8.1%).
There were no significant differences between the groups in the secondary end-points of the primary endpoint plus cath-eterization without obstructive CAD (HR = 0.91; 95% CI, 0.78-1.06) and death or non-fatal MI (HR = 0.88; 95% CI, 0.67-1.15), Douglas said.
The median cumulative radiation ex-posure per patient was 10 mSv in the CTA group and 11.3 mSv in the functional test-ing group, but because 32.6% of patients in the functional testing group had no expo-sure, the overall exposure was higher in the CTA group (mean, 12 mSv vs. 10.1 mSv; P < .001).
Daniel B. Mark, MD, MPH, and col-leagues conducted an economic substudy of PROMISE to assess economic outcomes and cost effectiveness of the two approach-es. Mark, professor of medicine at Duke Clinical Research Institute and the Duke Heart Center, and colleagues analyzed ini-tial diagnostic test technical fees, hospital-based facility costs and doctor fees.
“A bit of a controversy has broken out in the field,” he said during the press confer-ence. “The pro side says CTA would allow precision care and would allow only the patients who would need revasculariza-tion to go to the cath lab. Everybody else
Originally posted on Healio.com/Cardiology | March 14, 2015
PRoMise: CTa, functional testing associated with similar outcomes in patients with suspected CaD
PERSPECTIVE
The PROMISE trial found there is really no difference whether you use CT angiogram or you use functional testing; it’s sort of the difference between anatomic testing and functional testing. It’s important to note that the trial did not meet the noninferior-ity endpoint, despite the results showing no difference in the two treatment arms. But what is interesting is seeing there may be a rule for the usefulness of CT angiogram, and that is really what we haven’t known. To date, no insurers are covering CT an-giograms. Patients are often paying out of their own pockets, and this might be a way for us to reduce doing cardiac catheter-izations on people who have nonobstructive coronary disease
because that was one of the findings. Patients who underwent CT angiogram were less likely to find nonobstructive coronary disease, meaning we’re doing the catheteriza-tions on the right people. On the other hand, we’re certainly getting more radiation when we use CT angiograms, and there are cost considerations to take into account. The fact is that often the people who had a CT angiogram were also going under other types of stress testing. It’s important for our insurers and patients know these findings, which could potentially change how we treat patients and maybe cover the tests if it is going to save us money in the long run.
Martha Gulati, MD
Director, Preventive Cardiology and Women’s Cardiovascular Health
Ohio State University
Disclosure: Gulati reports no relevant financial disclosures.
Martha Gulati
“Coronary CTa may not be the holy grail of cardiology, but following the PRoMise standards … [it] will definitely improve some aspects of care without causing a major new economic armageddon in the health care system.”DanieL b. MaRk, MD, MPH
would avoid the need for an invasive test and could be managed noninvasively, so they wouldn’t get extra revascularization, false positives would be reduced and costs would be reduced. The con side says CTA would increase noninvasive and invasive testing, because a lot of the findings on the CTA would be ambiguous, and doctors would want to be certain, so they would do more tests, there would be more radiation exposure and more cost.”
Researchers estimated initial testing costs as $404 per person for CTA, $501 to $514 per person for stress echocardiogra-phy, $174 per person for exercise electro-cardiography and $946 to $1,132 per per-son for nuclear stress testing.
However, when the researchers calcu-lated cumulative total costs by intention to
treat and mean cost difference, they found that total costs per person for CTA were slightly more than costs for functional test-ing: $279 at 3 months, $358 at 12 months, $388 at 24 months and $694 at 36 months. The jump from 24 months to 36 months was primarily explained by some outlier patients in the CTA group who required non-CV care, and the other differences were explained by increased revasculariza-tion in the CTA group, Mark said.
“Coronary CTA may not be the holy grail of cardiology that we hoped it would be, but its more liberal use following the PROMISE standards … will definitely im-prove some aspects of care without causing a major new economic Armageddon in the health care system,” Mark said. – by Erik Swain n
References:Douglas PS, et al. ACC.15 Opening Showcase and the Joint ACC/JACC Late-Breaking Clinical Trials.
Douglas PS, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1415516.
Mark DB, et al. Joint ACC/JAMA Late-Breaking Clinical Trials.
Disclosures: The study was funded by the NHLBI. Douglas reports receiving research grants or contracts to her institution from Abiomed, Bris-tol-Myers Squibb, Edwards Lifesciences, Gilead, HeartFlow, Ikaria/Bellerophon, ResMed, Roche and Stealth Peptides, and receiving royalties from UpToDate/Kluwer. Mark reports receiving grant support from AGA Medical, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gilead and Oxygen Thera-peutics and consulting for CardioDx, Medtronic, Milestone and St. Jude Medical.
ProMiSeProspective Multicenter Imaging Study for Evaluation of Chest Pain
Researchers studied outcomes of anatomical vs. functional testing for CAD.
Design: randomized, prospectivePatients: 10,003Centers: 193Countries: Canada, United States
RESULTS: The composite primary endpoint of death, MI, hospitalization for unstable angina or major procedural difficulties occurred in 3.3% of patients assigned coronary CT angiography vs. 3% assigned functional testing (adjusted HR = 1.04; 95% CI, 0.83-1.29) during a median follow-up of 25 months. CTA was associated with fewer catheterizations showing no obstructive CAD. There was no difference between CTA and functional testing in secondary endpoints of the primary endpoint plus catheterization without obstructive CAD.Douglas PS, et al. ACC.15 Opening Showcase and the Joint ACC/JACC Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Sessions; March 14-16, 2015; San Diego.
cardiology today
iMAgingPERSPECTIVE
This was an interesting trial that will significantly impact how we care for patients who we see every day. The PROMISE trial included 10,000 patients who were randomized to have func-tional testing for the evaluation of chest pain with either an ex-ercise tolerance test, nuclear imaging or stress echo vs. a group that had CT angiograms. Based on the testing, the determinant looked at the primary endpoint which included all-cause mor-tality, CV hospitalization, MI or undergoing a cardiac catheteriza-tion within 90 days.
The trial demonstrated there really wasn’t any significant differ-ence as to how you approach these patients. All of these patients
were low-to-intermediate risk presenting with chest discomfort. The group that had the CT angiogram as their diagnostic tool had a 3% primary endpoint. The other group had 3.3%, which was not statistically significant.
Secondary endpoints included undergoing cardiac catheterization at 90 days, looking at the importance of radiation exposure as well as looking at what their management strategy should be. It’s important as we determine how we’re going to manage these individuals that we see everyday that we realize the treatment strategies we choose do not appear to make a whole lot of difference. Patients who underwent CT angiogram were more likely to undergo cardiac catheterization but were also less likely to have obstructive coronary artery disease. Patients who underwent functional testing had more diagnostic procedures, but the outcomes were basically the same for the primary endpoint.
This gives us some opportunities to be very comfortable with whichever resources are available at our facilities; knowing that patients will be well-cared for and the out-comes very similar, whether we’re doing regular exercise tolerance testing or stress echo vs. the newer technologies with CT-guided angiograms. It’s important as we try to make very careful and important decisions about which financial resources we’re going to utilize to care for our patients that we know we’re providing good care for all of those that we see and that whichever strategy we use will probably be OK.
Paul L. Douglass, MD
Cardiology Today Editorial Board Member
Disclosure: Douglass reports no relevant financial disclosures.
Paul L. Douglass
Read more executive summaries of the latest important cardiology trials at Healio.com/Cardio/TrialScorecards.
Trial Scorecard
6 | june 2015 | Healio.com/Cardiology
At 5 years, a balloon-expandable transcatheter aortic valve replace-ment system and surgical aortic
valve replacement were associated with similar outcomes in high-risk patients and with better outcomes than standard care in inoperable patients with severe aortic stenosis, according to final results of the PARTNER 1 trial.
High-risk patientsMichael J. Mack, MD, chairman of car-
diovascular medicine and surgery at the Baylor Scott and White Health Care System, Dallas, and colleagues enrolled 699 patients with severe aortic stenosis at high risk for surgery in the PARTNER 1 trial.
They randomly assigned 348 patients to TAVR with a balloon-expandable bovine pericardial tissue valve (Sapien, Edwards Lifesciences) by a transfemoral or transapi-cal approach, and 351 to surgical AVR. Mean Society of Thoracic Surgeons Predicted Risk of Mortality Score was 11.7%.
At 5 years, risk for death was 67.8% in the TAVR group vs. 62.4% in the surgical AVR group (HR = 1.04; 95% CI, 0.86-1.24), Mack, a member of the Cardiology Today’s In-
tervention Editorial Board, and colleagues reported.
At 5 years, TAVR and surgical AVR were similar in risk for stroke (HR = 1.14; 95% CI, 0.68-1.93) and all-cause mortality or stroke (HR = 1.09; 95% CI, 0.9-1.31).
The researchers observed no structural valve deterioration requiring surgical valve replacement in either group.
“There was an increase in stroke rate initially associated with TAVR compared to surgical aortic valve replacement,” Mack said during a press conference. “By the time we got out to 2 years, those lines converged, and there was no difference in [the] 5-year stroke rate between the two approaches.”
In other 5-year results, moderate or se-vere aortic regurgitation occurred in 14% of the TAVR group vs. 1% of the surgical AVR group (P < .0001).
Moderate or severe aortic regurgitation was associated with increased 5-year risk for
mortality in the TAVR group (moderate or severe aortic regurgitation, 72.4%; mild aortic regurgitation or less, 56.6%; P = .003).
“The 5-year follow-up to this trial sup-ports that TAVR is [an] alternative to sur-gery in high-risk patients, with similar mortality and other clinical outcomes,” Mack said. “Functional outcomes were also similar, with improvements in both valve function maintained in both groups with no evidence of structural valve deterioration.”
with severe symptomatic inoperable aortic stenosis (mean age, 83 years; 54% women; mean Society of Thoracic Surgeons Predict-ed Risk of Mortality Score, 11.7%).
They assigned 179 patients to TAVR with the balloon-expandable valve and 179 to standard treatment, often including balloon aortic valvuloplasty.
Risk for all-cause mortality at 5 years was 71.8% in the TAVR group vs. 93.6% in the standard treatment group (HR = 0.5; 95% CI, 0.39-0.65), according to the re-searchers.
At 5 years, only six patients in the stan-
Originally posted on Healio.com/Cardiology | March 15, 2015
PaRTneR 1: TavR equivalent to surgery in high-risk patients, better than standard care in inoperable patients
PERSPECTIVE
The PARTNER 1 trial was among five late-breaking clinical tri-als grouped together based on being appropriate with regards to valve disease and interventions. This PARTNER trial gives us 5-year results.
We saw in results from the initial 1-, 2- and 3-year results that sur-gery vs. percutaneous valve in high-risk populations had equiv-alent outcomes, both for survival and procedural complications. For the 5-year data, one of the important pieces of this trial was durability.
The concerns about these percutaneous valves are: Do they have the same long-term durability when we look at them?
Is there any fall-off in either valve dysfunction or in morbidity or mortality in these patients? This is very important data to put those questions into context.
Athena Poppas, MD
Chair, American College of Cardiology Annual Scientific Session
Disclosure: Poppas reports no relevant financial disclosures.
Athena Poppas
“The 5-year follow-up to this trial supports that TavR is [an] alternative to surgery in high-risk patients, with similar mortality and other clinical outcomes.”MiCHaeL J. MaCk, MD
dard treatment group did not die, cross over to TAVR or withdraw from the study; five had aortic valve replacement treatment outside the study.
Also at 5 years, 86% of survivors in the TAVR group had NYHA class I or II HF symptoms vs. 60% of survivors in the standard-treatment group, according to the researchers.
Those in the TAVR group alive at 5 years showed durable hemodynamic benefit (aortic valve area, 1.52 cm2; mean gradient, 10.6 mm Hg) with no evidence of structur-al valve deterioration.
The SAPIEN valve is approved in the United States for inoperable and high-risk operable patients.
Patients in the TAVR group of the PARTNER trial will be followed annually for life in the Society of Thoracic Surgeons/American College of Cardiology Trans-catheter Valve Therapies registry. – by Erik Swain n
References:Kapadia SR, et al. Lancet. 2015;doi:10.1016/S0140-6736(15)60290-2.
Mack MJ, et al. Late-Breaking Clinical Trials III.
Mack MJ, et al. Lancet. 2015;doi:10.1016/S0140-6736(15)60308-7.
Disclosure: The study was funded by Edwards Lifesciences. Mack reports receiving travel reim-bursement from Edwards Lifesciences relating to his position as an unpaid member of the PARTNER trial executive committee.
PERSPECTIVE
What is remarkable is how identical the curves look over time. It’s striking that the outcome in this very high-risk group of pa-tients who either went to surgery or had TAVR were essentially the same. There are very slight differences, but the important thing about this trial is that it shows the percutaneously im-planted valves are durable and that the outcome at 5 years is no different than it is at 1 year. A concern at the outset was whether this valve would be durable. This shows definitively that it is. What it means for the high-risk patients is that this is an excel-lent alternative and clearly may be preferred by patients.
The presence of paravalvular leak was associated with a slightly poorer outcome. Conversely, the subset who did not have para-
valvular leak demonstrated slightly better outcomes than the surgically implanted valves. Paravalvular leak clearly impairs results. The good news, however, is that these were first-generation devices. In all of the newer generations — and there are now ap-proximately 30 valve companies working on iterations — they are lower profile with a better seal around the outskirts of the valve so that there is less chance of paravalvular leak.
In the device and interventional world, it is notable to have a first-generation device such as this initial SAPIEN valve to demonstrate equal results compared with an exist-ing therapy that has a much longer track record, but is significantly more invasive. The 5-year results from the PARTNER trial confirm the fact that this is a game-changing therapy. Valve replacement will continue to trend toward minimally invasive tech-niques. I think we will never look back.
I appreciated that Michael Mack gave a nod to two very important people in the field who are no longer with us: Donald S. Baim, MD, and Michael J. Davidson, MD. The premature loss of both of them, Don from cancer and Michael from a gunshot wound, represents a loss for their families and friends, but also for the entire field of CVD. They will be remembered.
Kenneth Rosenfield, MD, MHCDS, FACC, FSCAI
Cardiology Today’s inTervenTion Editorial Board Member
Disclosure: Rosenfield reports no relevant financial disclosures.
Kenneth Rosenfield Nathaniel Reichek, MD, director of
cardiac imaging services at St. Francis Hospital, Roslin, NY, offers his perspec-tive on data from the PROMISE trial.
William T. Abraham, MD, director of the division of cardiovascular medicine at Ohio State University, highlights ad-vances in interventional heart failure.
Sanjeev Bhavnani, MD, of the division of cardiology, Scripps Health, San Diego, Calif., shares how the union of science and technology is changing the field.
Video PerSPectiVeS
Watch these videos and others from the meeting in our resource center at Healio.com/DiscoveriesACC.
Originally posted on Healio.com/Cardiology | March 14, 2015
PeGasus–TiMi 54: Ticagrelor improves outcomes in patients at least 1 year after Mi
T reatment with ticagrelor reduced the risk for CV death, MI or stroke in patients with MI within the previous
1 to 3 years, according to results from the PEGASUS–TIMI 54 study.
Those patients assigned ticagrelor (Bril-inta, AstraZeneca) had an increased risk for major bleeding, however.
Marc S. Sabatine, MD, MPH, from the TIMI Study Group, cardiovascular medicine division, Brigham and Women’s Hospital and Harvard Medical School, and colleagues investigated whether there is a benefit to dual antiplatelet therapy (DAPT) with ticagrelor and aspirin beyond 1 year after MI.
The researchers enrolled 21,162 pa-tients who had MI within the previous 1 to 3 years in the PEGASUS–TIMI 54 study. All patients received low-dose aspirin and were randomized on a 1:1:1 basis to receive twice-daily doses of ticagrelor 90 mg, ti-cagrelor 60 mg or placebo. Median follow-up was 33 months.
The primary efficacy endpoint was a composite of CV death, MI or stroke. At 3 years, the Kaplan-Meier rates of the pri-mary efficacy endpoint were lower with ti-cagrelor vs. placebo.
“With the addition of this antiplatelet drug, the curves start to diverge early, and they continue to separate out over time, further supporting the notion of long-term DAPT with aspirin and ticagrelor in these individuals,” Sabatine said during a press conference. “The benefit of ticagrelor was consistent for both the fatal and nonfatal components of the primary endpoint. It was consistent over the duration of treat-ment and amongst the major clinical sub-groups.”
The primary safety endpoint was TIMI major bleeding. Rates of TIMI major bleed-ing were higher in those assigned ticagre-lor. However, the rates of nonfatal intra-cranial hemorrhage or fatal bleeding were similar between those assigned ticagrelor or placebo.
“[This trial] confirms what we saw in a CHARISMA study group many years ago with respect to patients at high athero-thrombotic risk benefiting from long-term DAPT … [and] shows that ticagrelor seems to be of benefit beyond 1 year,” Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs and Brigham and Women’s Heart and Vascular Center, professor of medicine at Harvard Medical School and Chief Medical Editor of Cardiology Today’s Intervention, said in an interview. – by Erik Swain n
References:Bonaca MP, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1500857.Sabatine MS, et al. ACC.15 Opening Showcase and the Joint ACC/JACC Late-Breaking Clinical Trials.
Disclosure: The study was funded by AstraZeneca. Sabatine reports financial ties with Abbott Labora-tories, Accumetrix, Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Critical Diagnostics, Cubist, CVS Caremark, Daiichi Sankyo, Eisai, Genzyme, Gil-ead, GlaxoSmithKline, Intarcia, Merck, MyoKardia, Nanosphere, Pfizer, Quest Diagnostics, Roche Di-agnostics, Sanofi-Aventis, Takeda, Vertex and Zeus Scientific, and two pending patents related to the results of the study. Bhatt was on the PEGASUS-TIMI 54 executive committee and was involved in the de-sign and execution of the study.
PERSPECTIVE
The PEGASUS trial showed us that the use of ticagrelor in pa-tients who have had ACS extended out over a year resulted in a significant reduction in CV risk when compared with aspirin alone. In the study, two different dosages of the drug were com-pared along with aspirin alone. In both of the dosage cases aspi-rin was utilized as well.
The findings showed a reduction in the endpoints of death and MI and a slight increase in risk of bleeding. Between the two dif-ferent dosages, the reduction in risk was very similar. The reduc-tion in the risk of bleeding was a bit higher in the higher dose.
This is really interesting information for clinicians and backs up some of the prelimi-nary data that we’ve had from other studies suggesting that the use of DAPT may be beneficial in this type of patient.
Richard A. Chazal, MD
Vice President, American College of Cardiology
Disclosure: Chazal reports no relevant financial disclosures.
This study demonstrated that long-term use [of DAPT] improves outcomes. We knew it at least up to 12 months, but this longer-term trial did show a significant difference. The issue is, will the same be true with a generic drug such as clopidogrel? But this will give clinicians something to think about when they have dis-cussions with their patients about the use of maintenance medi-cations to reduce risk. Ticagrelor has not been used aggressively across the country, but this will give physicians another option to look at, although the downside of bleeding risk will need to be considered.
The findings are going to stimulate physicians to think about the issue of maintenance therapy with DAPT in a different light. Each patient will need to be individualized with this new body of knowledge.
John Gordon Harold, MD, MACC
Past President, American College of Cardiology
Disclosure: Harold reports no relevant financial disclosures.
9 | MAY 2015 | Healio.com/CT | june 2015 | Healio.com/Cardiology
T he third generation of a balloon- expandable transcatheter aortic valve replacement system showed favorable
30-day outcomes compared with previous generations, according to findings pre-sented.
The trial evaluated the next-genera-tion, balloon-expandable SAPIEN 3 valve (Edwards Lifesciences) in a cohort of high-risk, inoperable and intermediate-risk patients.
The study included two separate, sin-gle-arm registries, including 583 high-risk and inoperable patients with severe aortic stenosis in one arm and 1,076 intermedi-ate-risk patients in the second arm.
“That is the first time that we have any data in the U.S. on intermediate-risk patients,” Susheel Kodali, MD, of Colum-bia University Medical Center, New York-Presbyterian Hospital, told Cardiology Today.
Made of cobalt chromium, the SAPIEN 3 valve is distinguished by a cuff on the outer side encompassing the lower third of the valve, designed to seal in the annu-lus and reduce paravalvular leak (PVL), as well as a new frame geometry, he said.
Patients in the high-risk cohort had a 30-day all-cause mortality rate of 2.2%, below the predicted 8.6% rate.
“That is dramatically lower than the mortality predicted with surgery and dra-matically lower than we’ve seen in any other high-risk cohort with transcatheter aortic valve replacement,” Kodali said.
The mortality rate among intermedi-ate-risk patients was 1.1%, which was low-er than the predicted rate of 5.3%. Stroke rates were also low, with disabling stroke occurring in 0.9% of the high-risk cohort and 1% in the intermediate-risk cohort.
“The stroke rates were one of the more surprising results from this study, for my-self and for a lot of the investigators,” Kodali said. “These are the lowest stroke rates that we’ve seen in any trial, and these are stroke rates with a high degree of oversight.”
Strokes were adjudicated by neurolo-gists who evaluated the patients before, during and after an event.
Both major vascular complications and major bleeding risk were rare, in the range of 5% to 6%, Kodali said. Permanent pace-maker rates were slightly higher than ear-lier generations, with 13% in the high-risk
cohort and 10.1% in the intermediate-risk cohort.
In echocardiograms read by a core lab, the rate of moderate PVL was 3.7% and se-vere PVL 0.1%, much lower than previous iterations of transcatheter valve.
“For the SAPIEN and SAPIEN XT de-vices in earlier trials, the moderate to se-vere PVL rates were anywhere from 11% to 24%,” Kodali said.
The low mortality and stroke rates ob-served among intermediate-risk patients in these early results are likely to “start changing the conversation” as long-term follow-up data emerges, he said, and sug-gest that TAVR may be a better option than surgery in this population, particu-larly among patients aged over 80 years.
“This is an early look at the data, we’re going to continue to follow these patients. “As we get to 1, 2 and 5 years, we’re going to be really interested in what we see.” – by Adam Taliercio and Allegra Tiver n
Reference:Kodali S. Late-Breaking Clinical Trials III.
Disclosure: Kodali reports receiving research/grant support from Boston Scientific, Claret Medi-cal, Edwards Lifesciences and Medtronic; serving on steering committees for Claret Medical, Ed-wards Lifesciences and Meril and honoraria from Claret Medical and St. Jude Medical; and holding equity in Thubrikar Aortic Valve Inc.
Originally posted on Healio.com/Cardiology | April 17, 2015
Third-generation balloon-expandable TavR system linked to lower death, stroke rates
PERSPECTIVE
The late-breaking clinical trials presented were very exciting, particularly one dealing with the SAPIEN 3 device, an Edwards Lifesciences transcatheter aortic valve replacement prosthe-sis. It is of much smaller size than the first generation Edwards device and as a result, delivery is safer and easier to perform.
We learned there was a serial reduction in 30-day death rates following TAVR compared with the first-generation devices. We find ourselves in an era in which TAVR may very well be applied to intermediate surgical-risk patients with very low periproce-dural mortality and stroke complication rates. Generally, both of those now seem to be in the range of 1% compared with rates
as high as 5% and 6% just several years ago.
Patrick O’Gara, MD
President, American College of Cardiology
Disclosure: O’Gara reports no relevant financial disclosures.
Patrick O’Gara
“These are the lowest stroke rates that we’ve seen in any trial, and these are stroke rates with a high degree of oversight.”susHeeL koDaLi, MD
10 | june 2015 | Healio.com/Cardiology
T he PCSK9 inhibitor evolocumab in ad-dition to standard care was associated with significant reductions in LDL and
lower risk for CV events, according to com-bined data from the OSLER-1 and -2 trials.
The two open-label trials incorporated a total of 4,465 patients (n = 1,324 for OSLER-1 and n = 3,141 for OSLER-2) who had com-pleted at least one of the prior 12 trials of evo-locumab (Amgen). After 12 weeks of treat-ment, LDL decreased 61%, from a median of 120 mg/dL at baseline to 48 mg/dL among evolocumab recipients vs. nonrecipients (P < .001). Overall, 90.2% of the evolocumab group reached LDL levels < 100 mg/dL at 12 weeks vs. 26% of the standard therapy group, and levels < 70 mg/dL in 73.6% and 3.8% of cases, respectively (P < .001 for both). The observed reductions in LDL persisted during the course of the study.
Participants were randomly assigned 2:1 to receive standard therapy either alone or with subcutaneous evolocumab 140 mg every 2 weeks for 56 weeks (OSLER-1) or 420 mg monthly for 48 weeks (OSLER-2). The primary endpoint was prevalence of adverse events, and the secondary endpoint was percent change in LDL. Follow-up was conducted during a median of 11.1 months.
The incidence of CV events at 1 year was significantly lower in the evolocumab group vs. the standard-therapy group (2.18% vs. 0.95%; HR = 0.47; 95% CI, 0.28-0.78). This effect was consistent across all evaluated CV event types, as well as across different types of patients.
According to a press release, a larger, ongoing trial of 27,500 patients will evalu-ate the effect of evolocumab on CV out-comes, with results expected in 2017.
“These data now give us a sense for the po-tential clinical benefit of these drugs,” Marc S. Sabatine, MD, MPH, from the TIMI Study Group, cardiovascular medicine division, Brigham and Women’s Hospital and Harvard Medical School, said in the release. “We know from previous research that evolocumab lowers LDL cholesterol, but these data offer
support for [its] potential to reduce major ad-verse CV events in our patients.” – by Adam Taliercio and Erik Swain n
References:Sabatine MS. Joint Session of the ACC/JAMA Late-Breaking Clinical Trials.
Sabatine MS, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1500858.
Disclosures: Sabatine reports receiving con-sultant fees and/or honoraria from Amgen, As-traZeneca, Cubist, CVS Caremark, Intarcia, Med-scape, Merck, MyoKardia, Vox Media and Zeus Scientific; and conducting research for or receiv-ing research grants from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Dai-ichi-Sankyo, Eisai, Gilead Sciences, Glaxo-Smith-Kline, Intarcia, Merck, Roche Diagnostics, Sanofi and Takeda Pharmaceuticals.
Originally posted on Healio.com/Cardiology | March 16, 2015
osLeR studies indicate long-term safety, efficacy of evolocumab for LDL reduction
PERSPECTIVE
This is a very exciting time. We have mounting information now of PCSK9 inhibitors. These monoclonal antibodies are injectable every 2, 4 or even 8 weeks and dramatically lower LDL cholesterol with a very good safety profile. The agents cause some allergic reactions of the skin, as you might imagine, related to the injections, but are very tolerable. We saw in the late-breakers emerging data in rela-tively small randomized controlled trials not designed to address the issue of reduction of CV events; yet in these underpowered, relatively small studies, it appears events are trending down, so this is very gratifying. It gives us renewed enthusiasm to look forward to the phase 3 trials that will be coming out at the end of the next 2 years. One will likely be approved soon, probably by next year, for
familial hypercholesterolemia, which remains problematic in Caucasian populations and seen in 1 in 500 people. In cardiology practices, the prevalence is higher because of the referral bias of seeing people with CVD, so we’re very excited about this. Nevertheless, we need to await these phase 3 clinical trials and hope they will be positive, and hope the agents will be approved for the management of not only familial hypercholesterolemia but also CVD. The big elephant in the room is cost. Likely, because of the extensive R&D, these will be priced expensively. Yet, we might remain hopeful with so many competitors driving to this FDA approval; some competition is usually good for the consumer.
C. Noel Bairey Merz, MD, FACCCardiology Today Editorial Board Member
Disclosure: Bairey Merz reports receiving consulting honoraria from Amgen and Pfizer.
The results reported from the OSLER follow-up study for the PCSK9 inhibitor evolocumab, a monoclonal antibody, are of great interest. The PCSK9 inhibitors, when added to statins, lower LDL cholesterol another 60% or so. But for the first time we have found out that addi-tional LDL-lowering inhibitors from PCSK9 inhibitors further reduce CV events by about 50%. We know statins are first line of therapy; it is recommended in recent ACC/AHA guidelines to really maximize statin therapy. But we know a lot of people can’t tolerate maximum-dose statin therapy, or it may not be effective enough for them. This will be yet another drug that we can add to further lower LDL and hopefully reduce CV events in these high-risk patients.
Jennifer G. Robinson, MD, MPHProfessor of Epidemiology and Internal Medicine, University of Iowa
Disclosure: Robinson reports receiving consulting honoraria and research funding from multiple companies and institutions.
C. Noel Bairey Merz
Jennifer G. Robinson
11 | MAY 2015 | Healio.com/CT | june 2015 | Healio.com/Cardiology
A s the ACC Scientific Sessions were underway in San Diego, the FDA ap-proved a left atrial appendage closure
device as an alternative to warfarin therapy to reduce the risk for thromboembolism in pa-tients with nonvalvular atrial fibrillation.
The Watchman (Boston Scientific Corpo-ration) functions by closing the left atrial ap-pendage in order to prevent blood clots from migrating.
The approval was based on results from the Watchman clinical program, which in-cluded data from more than 2,400 patients over approximately 6,000 patient-years of follow-up. Favorable results from trials in-cluding PROTECT AF and PREVAIL sug-gested that the device was a safe and effective alternative to warfarin. In December 2011, the FDA Circulatory System Devices Panel voted 13-1 that the benefits of the Watchman device outweighed its potential risks.
A second vote in October 2014 resulted in a split: panelists voted 12-0 that the device was safe, 6-7 that it was not effective and 6-5 that its benefits outweighed its risks. How-ever, the panel reached a consensus that the device should only be considered a second-line therapy for certain patients.
With this approval, the device is indicat-ed for patients who are deemed suitable for warfarin but have “an appropriate rationale to seek a non-pharmacologic alternative,” ac-cording to the release.
“We know that up to 40% of patients who are eligible for oral anticoagulation do not take it for numerous reasons, highlighting the need for additional treatment options,” Vivek Y. Reddy, MD, director of the cardiac arrhyth-
mia service at Mount Sinai Medical Center, who served as co-principal investigator of the PROTECT AF and PREVAIL trials, said in the release. “The Watchman device is a break-through treatment providing those patients who are suitable for warfarin with an implant-based alternative to long-term warfarin thera-py while still reducing the risk of stroke.”
The device has been available internation-
ally since 2009. Following this approval, it will be available at U.S. centers that participated in the clinical trial program, and will later be introduced into other specialized facilities as physicians receive training for its implan-tation, according to the release. – by Adam Taliercio n
Disclosure: Reddy reports receiving grant sup-port and consultant fees from Boston Scientific.
PERSPECTIVE
A big development came along concurrently with the ACC meet-ing this year with the FDA approval of the Watchman left atrial appendage closure device for patients with nonvalvular AF who are suitable warfarin candidates but who have reason to seek out alternative approaches to stroke prevention. It’s important to step back and see how we can integrate left atrial appendage (LAA) closure into the treatment paradigm of our AF patients at risk for stroke.
A lot has been discussed already in prior meetings and publications about assessing a particular individual’s risk for stroke using such things as the CHA2DS2-VASc score, which has been endorsed by
clinical guidelines both in the U.S. and Europe. The Watchman device is an alternative treat-ment to reduce stroke in patients with AF who are warfarin candidates according to such a risk score. But the missing piece that one has to integrate into treatment decisions is the risk for bleeding. For example, the HAS-BLED Score, whose use is encouraged in European guidelines, can help assess the potential risk for bleeding over time, both on or off antico-agulation. We need to bring in the Watchman device into this conversation.
Overall, with the follow-up we have so far in the randomized trials, there do not appear to be differences in total bleeding risk with a Watchman device or warfarin; there is the procedure risk of the Watchman, whereas there is a bleeding risk over time with warfarin. What we found, and what I presented at [TCT and ACC], is that is a substan-tial bleeding advantage for the Watchman after completion of the required adjunctive pharmacotherapy after device implantation, about 6 months after the procedure.
So when we think about LAA, there are really three phases of risks for bleeding: proce-dural; during adjunct pharmacotherapy; and after one discontinues post-procedural anticoagulation and antiplatelet therapy. The longer the follow-up after Watchman implantation, the greater the benefit in that third phase.
We are appropriately focused on stroke risk when we make our treatment decisions, but I think we also need to incorporate bleeding risk into the equation. This requires a pretty deep discussion with our patients regarding their priorities, their preferences and their lifestyles. The Watchman device and other LAA closure devices under evalu-ation might help us achieve some balance for our patients. Although treatment de-cisions may feel complicated now that we have so many options available to us, for our patients, we have more options to individualize care, and I think that’s really the bottom line.
Matthew Price, MD
Cardiology Today’s inTervenTion Editorial Board Member
Disclosure: Price reports receiving speakers honoraria, consulting honoraria and research funding from multiple companies and institutions.
Originally posted on Healio.com/Cardiology | March 14, 2015
“The Watchman device is a breakthrough treatment providing those patients who are suitable for warfarin with an implant-based alternative.”vivek Y. ReDDY, MD
