March 16th, 2015
Better Than BEST? An Observational Comparison of PCI and CABG for Multivessel Coronary Disease
Sripal Bangalore, MD, MHA
The CardioExchange Editors interview Sripal Bangalore, lead author of an observational study comparing CABG with everolimus-eluting stent PCI in patients with multivessel coronary disease. The study was presented at the 2015 ACC conference and is published in the New England Journal of Medicine. It was paired with the publication of the BEST randomized trial, which compared the same interventions.
CardioExchange Editors: Is there an advantage that this observational study is being paired with the BEST trial in the NEJM and at ACC 2015?
Bangalore: Randomized trials (such as BEST) are the gold standard to test a hypothesis, but there are limitations. BEST, a noninferiority trial, was originally powered for a sample size of >1800 but enrolled only just over 800 patients. It is therefore a very underpowered study. Moreover, the primary endpoint was a composite that included repeat revascularization. From a clinical trials perspective, composite endpoints are helpful to reduce sample size and make the trial more manageable; from a clinical practice perspective, composite endpoints are problematic. The value that patients place on each component of the composite may differ from what physicians value (e.g., patients may value prevention of death and stroke more than repeat revascularization). In addition, composite endpoints are routinely misinterpreted. The BEST trial showed that during longer follow-up, PCI was associated with a higher risk for the primary outcome, but this result was driven only by an increase in repeat revascularization, not death.
Our study has a few strengths. The sample size was 22-fold higher than that of BEST (>18,000 vs. 800), and we were in a better position to look at individual outcomes rather than a composite endpoint. Remarkably, both studies have somewhat concordant results for individual endpoints:
- Death: no difference between PCI vs. CABG in either study
- MI: a higher rate with PCI than with CABG in both studies. However, our study showed that the higher rate of MI with PCI did not hold for patients who were completely revascularized.
- Repeat revascularization: a higher rate with PCI than with CABG in both studies
- Stroke: BEST showed no difference between PCI and CABG for this endpoint, at odds with our study and with findings from most PCI vs. CABG randomized trials, where CABG has shown a higher risk for stroke. Is this because of BEST’s small sample size and extreme lack of power for a low-frequency event, among other points that the authors outline?
- Our study also showed a higher risk for up-front death or stroke with CABG than with PCI, again concordant with prior studies. BEST did not report short-term outcomes.
CardioExchange Editors: What is the take-home point of your study for clinicians? How are the findings changing your practice?
Bangalore: The big take-home message from both studies is that, for mortality, the gap between PCI and CABG is narrowing: Both studies show no mortality difference between the two procedures. With the mortality benefit off the table, PCI and CABG are both reasonable options. Patients and physicians should weigh CABG’s up-front risk for death and stroke with PCI’s long-term risks for repeat revascularization and, perhaps, MI (among patients with incomplete revascularization).
JOIN THE DISCUSSION
How do the data from Dr. Bangalore’s study enhance your understanding of the findings from BEST?
To view all of our coverage from the ACC meeting, go to our ACC.15 Headquarters page.
March 16th, 2015
A Requiem for Routine Thrombectomy?
Larry Husten, PHD
Primary PCI is the treatment of choice in the early period of an acute MI. One limitation is the risk of dislodging part of the clot, leading to new downstream blockages of the microvasculature. One strategy that has been under development for a long time is thrombectomy, in which a device extracts the clot prior to the delivery of the stent. Following earlier success in small trials, the benefits of thrombectomy became controversial when a large trial, TASTE, found no evidence of benefit for the procedure.
TOTAL (Trial of Routine Aspiration Thrombectomy with PCI versus PCI Alone in Patients with STEMI), one of the largest trials ever to test a medical device, was presented at the American College of Cardiology meeting in San Diego and published simultaneously in the New England Journal of Medicine. The trial randomized 10,732 patients with acute ST- elevation MI undergoing primary PCI to routine upfront thrombectomy with the Medtronic Export catheter or no additional therapy. (The trial was investigator initiated but received funding from Medtronic.)
The primary outcome of the trial — a composite of CV death, recurrent MI, cardiogenic shock, or NYHA class IV heart failure within 180 days — occurred in 6.9% in the thrombectomy group versus 7% in the control group. There was still no difference when stent thrombosis and target vessel revascularization were added to the composite endpoint (9.9% versus 9.8%).
There was a small but statistically significant increase in the risk of stroke at 30 days in the thrombectomy group (0.7% versus 0.3%, HR 2.06, CI 1.13-3.75, p=0.02). This difference remained significant at six months. The investigators said that their stroke findings “cannot be easily explained.”
As in previous trials, the use of thrombectomy was associated with seemingly positive changes in surrogate outcomes, including improvement in ST-segment resolution and distal embolization. “This finding cautions against changing practice on the basis of trials showing an improvement in surrogate outcomes,” the authors wrote.
In an accompanying editorial, Filippo Crea writes that the stroke result “is difficult to interpret and is likely to be a chance finding…” The study was not powered to assess stroke. Further increasing doubt is the increased risk beyond the periprocedural period, he wrote.
But Crea says that the rigorous study design and large size lends credibility to the main findings of TOTAL. Although he suggests that it may be time “to prepare a requiem for routine manual thrombectomy” he said it is too early “to rule out the possibility that thrombus aspiration might be beneficial in high-risk patients.”
March 15th, 2015
Encouraging 5-Year Results for TAVR
Larry Husten, PHD
The publication five years ago of the two-part PARTNER trial brought a major change to the treatment of aortic valve replacement. The trial demonstrated that transcatheter aortic valve replacement (TAVR) was a reasonable treatment option, first for patients who were not surgical candidates and then for patients who were at high risk for surgery. One important lingering concern about TAVR was whether its results would prove to be sufficiently durable. Now the final five-year findings from the trial, published in two papers in the Lancet, provide strong reassurance regarding the durability of TAVR.
The first report was also presented at the American College of Cardiology meeting in San Diego. At five years TAVR maintained its superiority to standard treatment in patients with inoperable aortic stenosis with impressive improvements in mortality and heart function. At five years the all-cause mortality rate was 71.8% in the TAVR group versus 93.6% in the standard treatment group (HR 0.50, CI 0.39–0.65, p<0.0001). Eighty-six percent of TAVR patients (42 of 49) had NYHA class 1 or 2 symptoms compared with 60% (3 out of the remaining 5 patients) in the control arm.
The investigators concluded that “TAVR should be strongly considered for patients who are not surgical candidates for aortic valve replacement to improve their survival and functional status. Appropriate selection of patients will help to maximize the benefit of TAVR and reduce mortality from severe comorbidities.”
In the second report, at five years TAVR was still a reasonable alternative to surgery in the group of patients at high surgical risk. The five-year mortality rate was 67.8% in the TAVR group versus 62.4% in the surgery group (HR 1.04, CI 0.86–1.24, p=0·76). The investigators said that both the TAVR and surgical devices remained intact over five years and did not require surgical replacement. The rate of moderate or severe aortic regurgitation was 14% in the TAVR group versus 1% in the surgical group.
In an accompanying comment, Arie Kappetein writes that for patients not suitable for surgery TAVR is clearly superior to standard treatment but strongly recommends “a preoperative discussion between the heart team, patient, and other decision makers” to determine if TAVR is suitable for the individual patient. For patients at high surgical risk, “most patients will not consider the likelihood of a long-term benefit but instead choose the less invasive option.”
To view all of our coverage from the ACC meeting, go to our ACC.15 Headquarters page.
March 15th, 2015
More Information Emerges About the PCSK9 Inhibitors
Larry Husten, PHD
New information emerged today about two new cholesterol-lowering drugs that have been attracting a lot of attention. Data about the PCSK9 inhibitors — evolocumab, under development by Amgen, and alirocumab, under development by Sanofi and Regeneron — were presented at the American College of Cardiology meeting in San Diego and published simultaneously in the New England Journal of Medicine.
The effects of the two drugs appeared to be broadly consistent. Both lowered LDL cholesterol powerfully, which is what the drugs were designed to do. The situation is less clear regarding the more difficult to ascertain safety and tolerability of the drugs and their long-term clinical effects. On the one hand, the very early data suggest that the LDL-lowering effect may result in a substantial cardiovascular benefit. On the other hand, early signs hinting at adverse neurocognitive and other effects may put a brake on the so far unimpeded progress of the drugs through the FDA-approval process.
Evolocumab
Investigators presented combined results from two open-label randomized extension studies of evolocumab comparing two regimens of the injectable monoclonal antibody (140 mg every 2 weeks or 420 mg every month) plus standard therapy to standard therapy alone. A total of 4,465 patients were followed for 11.1 months. The trials were designed to obtain longer-term information about the safety and side-effect profile of the drug, and also to obtain a “prespecified exploratory analysis” of cardiovascular events.
As expected, evolocumab resulted in a large 61% reduction in LDL compared with standard therapy alone, from 120 mg/dl to 48 mg/dl. Overall, there was a similar rate of serious adverse events (7.5% in each group) but there was a small increase in neurocognitive events (0.9% versus 0.3%). The investigators noted that these events did not appear to be related to the reduction in LDL and further pointed out that the open-label design and the greater number of visits in the treatment group might have played a role. (However, one observer, Sanjay Kaul, said that it is also possible that the events are indicative of an off-target effect.)
The rate of cardiovascular events at one year was 0.95% in the evolocumab patients versus 2.18% in the control group (HR 0.47, CI 0.28-0.78, p=0.003). But, the investigators cautioned, the cardiovascular outcomes of the drug can not be fully determined until the completion of the ongoing, 27,500-patient FOURIER trial.
Alirocumab in ODYSSEY
ODYSSEY offered a similar look at the long-term effect of alirocumab. The trial was designed to assess the LDL-lowering effect and the long-term safety of alirocumab on 2,341 patients. In line with expectations, treatment with a 1 ml injection of alirocumab (150 mg) every two weeks resulted in a large 62% reduction in LDL compared to placebo. Overall, there were a similar number of adverse events in both groups but alirocumab was linked to an increase in some adverse events, including injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%).
The investigators also reported a post hoc analysis of major adverse cardiovascular events, consisting of cardiac death, nonfatal MI, stroke, or unstable angina requiring hospitalization. At 78 weeks the event rate was 1.7% in the alirocumab group versus 3.3% in the placebo group (HR 0.52, CI 0.31-0.90, p=0.02).
Editorial
In an accompanying editorial, Neil Stone and Donald Lloyd-Jones, both of whom served as co-authors of the recent cholesterol guidelines, write that the reduction in cardiovascular events with both drugs “whet our appetites for further results that show cardiovascular benefit and documented safety.” They express hope that, like statins, the beneficial effect will continue to grow over time.
But, they state, “it would be premature to endorse these drugs for widespread use before the ongoing randomized trials… are available.” Until these trials are finished they say that use of the drugs should fit within the recent guidelines, which recommend non-statin therapy in high-risk patients with persistently high LDL levels despite statin therapy or in people who are unable to tolerate statins.
To view all of our coverage from the ACC meeting, go to our ACC.15 Headquarters page.
March 14th, 2015
Has CT Angiography Lived Up to Its Early Promise?
Larry Husten, PHD
Computed tomographic angiography (CTA) enjoyed an explosion of growth over the past decade or more, fueled by enthusiasm for its ability to deliver speedy, high-resolution images of the coronary arteries. Many anticipated that CTA would prove its worth and justify its expense and radiation dose. As explained by one cardiologist, Duke University’s Dan Mark, with CTA “only the patients who needed revascularization would actually go to the cath lab and the rest would avoid it,” leading to a reduced use of invasive tests, fewer unnecessary revascularizations, fewer false positives, and, therefore, significant economic advantages. Many years later, however, there is still little agreement about CTA and how it should be used in the diagnosis and management of people with chest pain.
Results of the NHLBI-supported Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), presented at the American College of Cardiology meeting in San Diego and published simultaneously in the New England Journal of Medicine, provide the best evidence yet for the evaluation of CTA. The trial included 10,003 patients with chest pain randomized to CTA or functional exercise testing, consisting of either a standard exercise ECG test, a nuclear stress test, or stress echocardiography.
After two years the trial showed that CTA brought no improvement to the long-term outcome of the patients. The primary endpoint of the trial — the composite endpoint of death, MI, hospitalization for unstable angina, or major procedural complication — occurred in 3.3% of patients in the CTA group versus 3% in the control group. The results were consistent across different subgroups of patients.
A major goal of these procedures is to reduce highly invasive cardiac catheterizations. But within the first three months, 12.2% in the CTA group and 8.1% of the control group underwent cardiac catheterization. However, fewer patients in the CTA group who underwent catheterization were found to have no obstructive disease (27.9% in the CTA group and 52.5% in the control group).
The low number of events in the trial “probably reflects an excellent prognosis for patients with similar, new-onset, stable chest pain in real-world settings in which contemporary testing methods are used,” the authors wrote. “Showing a difference in patient outcomes with different testing strategies given this excellent midterm prognosis would require a large incremental test effect driving differences in downstream care or an extremely large study sample.”
“These findings highlight a substantial opportunity to improve the selection of patients for noninvasive testing beyond currently accepted approaches,” they wrote.
Although PROMISE didn’t provide a definitive answer to the role of CTA in clinical practice, it also didn’t give a broad endorsement to CTA, which makes doing CTA “less necessary,” said John Ryan. It “slows down the CTA train a little.”
In an accompanying editorial, Christopher Kramer terms the result a “tie” and asks how it will alter clinical practice.
Dan Mark, a PROMISE investigator who presented the results of the PROMISE economic substudy, said that CTA “may not be the ‘holy grail’ of diagnostic testing once hoped for” but that more liberal use “will improve some aspects of care without causing a major new economic burden on the health care system.” After more than two years of followup the use of CTA resulted in only a small, nonsignificant increase in cost (less than $500) and resulted in fewer patients going on to have an invasive cardiac catheterization with normal findings, he said.
The principal investigator of PROMISE, Pam Douglas, also at Duke, told CardioExchange that although they had expected CTA to lead to more catheterizations and revascularization procedures, “we were surprised by how much it improved the cath yield (rate of finding obstructive CAD at cath).” She said that CTA “is now proven to be a very viable alternative to functional testing. It should be considered as a first-line tool for patients with stable chest pain.”
To read our interview with Dr. Douglas about PROMISE click here, and to view all of our coverage from the ACC meeting, go to our ACC.15 Headquarters page.
March 14th, 2015
ACC.15 Headquarters
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CardioExchange is dedicated to bringing you the latest from ACC.15. Check out our coverage of the conference ─ then tell us what you think!
News:
- DAPT ‘Approaching the Point of Diminishing Returns’?
- Has CT Angiography Lived Up to Its Early Promise?
- More Information Emerges About the PCSK9 Inhibitors
- Encouraging 5-Year Results for TAVR
- A Requiem for Routine Thrombectomy?
- Folic Acid Supplementation Helps Reduce Stroke Risk in Certain Populations
Analysis:
- Assessing the Diagnostic PROMISE of CT Angiography
- Better Than BEST? An Observational Comparison of PCI and CABG for Multivessel Coronary Disease
Voices from San Diego:
- Learning Opportunities for Fellows-in-Training at ACC 2015
- Networking Opportunities and Cardiology Bootcamp at ACC.15
March 14th, 2015
Assessing the Diagnostic PROMISE of CT Angiography
Pamela S. Douglas, MD
The CardioExchange Editors interview Pamela S. Douglas, lead author of the PROMISE study. The randomized study compared CT angiography (CTA) with functional exercise testing (standard exercise ECG, nuclear stress testing, or stress echo) in more than 10,000 patients with chest pain. Findings were presented at the 2015 American College of Cardiology meeting and published simultaneously in the New England Journal of Medicine.
MAIN RESULTS
During a mean 25 months of follow-up, incidence of the primary endpoint — a composite of death, MI, hospitalization for unstable angina, or a major procedural complication — was 3.3% in the CTA group and 3.0% in the functional-testing group (a nonsignificant difference). Findings were consistent across various subgroups. Within the first 3 months, 12.2% of the CTA group and 8.1% of the control group underwent cardiac catheterization. Among randomized patients, a finding of no obstructive CAD was significantly less common in the CTA group than in the control group (3.4% vs. 4.3%).
Mean radiation exposure was lower in the stress-test group than in the CTA group (10.1 vs. 12.0 milliSieverts), because 33% had testing without any radiation exposure. Among patients initially intended for referral to nuclear stress testing, radiation exposure was lower in those randomized to CTA than to functional testing (mean, 12.0 vs. 14.1 mSv).
THE INTERVIEW
CardioExchange Editors: Were you surprised by the results of this study?
Douglas: There were a lot of surprises in this study, starting with the risk burden in the population. Given the considerable discussion about appropriate use, we expected to enroll a fairly low-risk group. Instead, the pretest likelihood of obstructive CAD was over 50%. Patients were middle-aged, had an average of 2.4 major CV risk factors, and were symptomatic — so they definitely required testing according to current guidelines.
The next surprise was the low event rate — much lower than previously reported in similar cohorts, and lower than predicted. Even so, that’s great news for patients. Given the event rate, it would have been very difficult to identify a difference between the groups.
Two of the secondary endpoints were surprising:
- We expected CT angiography to be associated with more caths and revascularizations, which it was, but we were surprised by how much it improved the cath yield (the rate of finding obstructive CAD at cath).
- We also expected radiation exposure to be higher with CTA than with nuclear testing, but the mean was more than 2 milliSieverts less.
CardioExchange Editors: Given the study’s findings, how are you changing your practice?
Douglas: CTA is now proven to be a very viable alternative to functional testing. It should be considered a first-line tool for patients with stable chest pain.
JOIN THE DISCUSSION
How will the findings from Dr. Douglas’ study alter your practice?
To view all of our coverage from the ACC meeting, go to our ACC.15 Headquarters page.
March 14th, 2015
DAPT ‘Approaching the Point of Diminishing Returns’?
Larry Husten, PHD
After a myocardial infarction (MI), patients remain at high risk for recurrent events. The precise role of dual antiplatelet therapy (DAPT) to lower this risk has been the subject of considerable disagreement. Now a new study offers fresh evidence that prolonged DAPT can lower risk over a long period, but only at the cost of more bleeding complications.
PEGASUS (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin – Thrombolysis in Myocardial Infarction [TIMI] 54), presented at the American College of Cardiology meeting in San Diego and published simultaneously in the New England Journal of Medicine, randomized 21,162 patients who had a heart attack 1 to 3 years previously to placebo or one of two doses (60 or 90 mg twice daily) of the thienopyridine ticagrelor (Brilinta, AstraZeneca).
After three years the rate of cardiovascular death, MI, or stroke was 7.85% in the high-dose ticagrelor group, 7.77% in the low-dose ticagrelor group, and 9.04% in the placebo group. When compared to placebo the result was highly significant for both ticagrelor groups.
However, the greater efficacy was achieved at the cost of a significant increase in bleeding. The rate of TIMI major bleeding was 2.6% with 90 mg ticagrelor, 2.3% with 60 mg ticagrelor, and 1.06% with placebo. There was no significant difference in intracranial hemorrhage or fatal bleeding.
Over the course of the trial the study drug was discontinued in 32% of patients in the high-dose ticagrelor group, 28.7% in the low-dose ticagrelor group, and 21.4% in the placebo group. One contributing factor was a higher rate of dyspnea in the ticagrelor groups (18.93% and 15.84% versus 6.38%).
In an accompanying editorial, John Keaney writes that the PEGASUS results “prompt speculation as to whether dual platelet inhibition with high-potency agents is approaching the point of diminishing returns.” He calculated that treating 10,000 patients with low-dose ticagrelor “for 1 year would prevent approximately 42 primary end-point events and produce approximately 31 TIMI major bleeding events — close to an even proposition.”
Although there were important differences between PEGASUS and last year’s DAPT trial, the trial investigators said that “broadly speaking, the two trials showed that prolonged P2Y12-receptor blockade reduced the rate of ischemic events and increased the rate of bleeding events among patients with coronary disease.” In his editorial, Keaney said that the results of the two trials were consistent with each other and “remind us of the fragile balance between efficacy and adverse events.”
To view all of our coverage from the ACC meeting, go to our ACC.15 Headquarters page.
March 14th, 2015
FDA Approves Watchman Left Atrial Appendage Closure Device for AF
Larry Husten, PHD
The FDA has approved Boston Scientific’s long-delayed Watchman Left Atrial Appendage Closure Device. According to the company, the Watchman is indicated as an alternative to long-term warfarin therapy for the reduction of thromboembolism from the left atrial appendage in patients with non-valvular atrial fibrillation at increased risk for stroke and systemic embolism.
Although an alternative to warfarin, for patients to be eligible they must be “deemed by their physicians to be suitable for warfarin” and to have an “appropriate rationale” for preferring the device to warfarin.
Boston Scientific said the device will be available first at centers where it has been used in clinical studies. Availability will be more widespread as physicians are trained in its use.
The Watchman has a long and highly troubled history at the FDA. The FDA has postponed approval of the device on several occasions as it found numerous problems with the clinical trials exploring its use. Most recently, last October, the FDA’s Circulatory System Devices advisory panel gave the device an extremely cautious endorsement. They said the trials supporting the device, PROTECT AF and PREVAIL, clearly showed that Watchman was not equivalent to warfarin. But they also felt that the device should be made available to AF patients who were eligible for but did not want to take warfarin.
March 10th, 2015
First Good Look at TAVR in The Real World
Larry Husten, PHD
Transcatheter aortic valve replacement (TAVR) is one of the most important advances in cardiovascular medicine in recent years. Although it is associated with significant risks, TAVR can offer some patients a less invasive alternative to traditional aortic valve replacement surgery. Because of early concerns about potential overuse and misuse of TAVR, many observers have been eagerly awaiting information about its use in the real world.
Now a new report published in JAMA offers the best perspective yet on the introduction of TAVR in the US with an analysis of the one year outcomes of the first group of patients who underwent the procedure. The researchers linked records from 12,182 patients who were enrolled in the Society of Thoracic Surgeons/American College of Cardiology (STS/ACC) Transcatheter Valve Therapies Registry with outcomes data from CMS.
The major finding of the study was that at 1 year slightly more than a quarter of the patients (26%) had died or had a stroke. The death rate was 7% at 30 days and 23.7% at 1 year. The stroke rate was 2.5% at 30 days and 4.1% at 1 year. More than half of the patients (53.2%) were readmitted to the hospital at least once in the year following their procedure.
The report makes clear that this was a very sick group for whom TAVR was offered because the patients were considered to be at high surgical risk. The patients were old (mean age, 84) and fragile. Most had advanced heart failure (82.5% had New York Heart Association class III or IV) and other comorbidities. The risk of death at 1 year was linked to older age, male sex, end-stage renal disease and severe chronic obstructive pulmonary disease. Women had a higher risk of stroke than men.
The authors point out that although the study included “only patients considered to have high risks with AVR, the majority of this mortality does not represent periprocedural complications, as 30-day mortality was only 7.0 percent. As such, this makes it imperative to focus on better prediction of the overall risks and benefits of the procedure, particularly given the existing comorbidities of the group of patients being considered for TAVR.” They write that “it may be possible to identify patients who may not benefit from this procedure and who should be counseled accordingly.”
Commenting on the study, Cedars-Sinai cardiologist Sanjay Kaul said that it “highlights the critical importance of patient selection in optimizing the benefit-risk balance of this important technology.” Kaul said that the relatively small number of patients who received TAVR during the study period represents less than a fifth of all surgical aortic valve replacements performed over the same period. “It is reassuring to witness this commitment to prudent and responsible dissemination of this technology by the stakeholders.”
Columbia University interventional cardiologist Ajay Kirtane said that the study “is the first look at disseminated use of TAVR here in the US across all sites performing the procedure commercially. Because of the requirement to participate in the TVT registry (for reimbursement through CMS), this registry represents all US commercial cases of TAVR during that time period. As such, the 30 day and one year mortality rates are what we would expect for this type of population. Ultimately, what is important is the continued recognition that this population is among the ‘sickest’ of the patients that we treat in cardiovascular medicine today, with late mortality that reflects the advanced age and numerous comorbidities of the population undergoing the procedure. I agree with the authors that this emphasizes the need for tools to predict more accurately which patients are chronically ill with aortic stenosis versus those who are ill because of aortic stenosis. The latter would appear to be the best candidates for TAVR, while the former would likely not be. We have definitely improved in our selection of patients for this procedure, especially as there are more lower-risk patients being treated now, but this also has important public health implications.”
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