Both the "extended" endpoint and death / MI are not different between weapons, but QoL is significantly better with PCI / CABG.
PHILADELPHIA, PA – After more than 10 years and $ 100 million, the International Comparative Study of Health and Invasive Health (ISCHEMIA) has yielded a decisive result: an invasive strategy in addition to optimal medical therapy (OMT) does not offers no benefit other than OMT only to prevent a number of major cardiovascular events in patients with stable to moderate to severe coronary disease.
This applies to the "extended" primary endpoint of cardiovascular death of ISCHEMIA, cardiovascular death, hospitalization for unstable angina, hospitalization for heart failure or resuscitation due to cardiac arrest ̵
"What do patients care about when seeking treatment? They are interested in living longer and feeling better, ”Judith Hohman, MD, PhD (NYU Langone Medical Center, New York, NY), told TCTMD. "At an average of 3.3 years of follow-up – and up to 5 years – overall there was no difference in their survival in this trial, but they felt better with the invasive strategy if they were angina at first. So this really is a perfect example of when we need to make shared decision-making between patients and their doctors. ”
Hohman, who directed the study with primary researcher David J. Maron, D.M. ) presented the main test results here today at the 2019 American Heart Association Scientific Sessions; Quality of Life (QoL) results were presented by Dr. John Sperthus (St. Luke's Heart Institute, Mid America, Kansas City, MO). Separately, Dr. Shripal Bangalore (Langone Medical Center, New York) presented the ancillary results of the ISCHEMIA-CKD trial, followed by QoL analyzes for this pre-determined ISCHEMIA study. Similar to the main study results, ISCHEMIA-CKD also did not benefit from an invasive approach over OMT in a population of patients with advanced chronic kidney disease and significant, stable coronary disease.
All experts who spoke with TCTMD said they were not particularly surprised by the results, but all had warnings.
Pamela Douglas (MD, PhD at Duke University, Durham, North Carolina) jokes that despite what people say, "Everything ISCHEMIA found would be a bit of a surprise, because there is really a balance feel "in their bones" about one thing or the other. "That said, she went on, it was not a" terrible "surprise that there was no difference in major outcomes, nor that there were more events at the beginning of the invasion group, which were then compared to later events in the Conservative Group – details provided by Hochman in it note today.  Finally ISCHEMIA
ISCHEMIA, conducted at 320 sites in 37 countries, enrolled 5 179 patients with stable CAD, persistent ejection fraction, and moderate to severe ischemia based on stress imaging or exercise tolerance test (ETT) ). Overall, more than 50% of patients in the study had severe inducible ischemia at baseline, 33% had moderate, and 12% had mild.
Patients were randomized to a strategy of invasive coronary angiography followed by revascularization, if necessary, of OMT or an initial conservative strategy of OMT alone. Randomization was performed before angiography and blind CT angiography (CTA) was performed in approximately two-thirds of the enrolled patient cohort to exclude life-threatening left underlying disease (or disease considered to be of comparable severity) and other acute problems such as aortic dissection or, in a smaller proportion of patients to check whether CAD is actually present. After all, 73% of randomized subjects have a CTA trial.
At a median of 3.3 years (in the range 2.2-4.4 years), the frequencies of the primary endpoint did not differ between the groups: 13.3% in the invasive group and 15.5% in the OMT group ( corrected HR 0.93; 95% CI 0.80-1.08). Event curves up to 5 years indicate that the conservative strategy had fewer CV events in the first 2 years, whereas the invasive strategy held the advantage between 3 and 5 years. The absolute difference between the groups in the two periods is approximately similar, resulting in equivalent results at final follow-up. The researchers hope to receive funding to continue to monitor patients for an additional 5 years.
For the major secondary endpoint of CV or MI death, event curves followed a similar pattern, passing around the 2-year mark, but again not significantly different at 4 years: 13.9% in the Conservative group versus 11.7 % in the invasive group (HR 0.90; 95% CI 0.77-1.06).
The rate of death for any reason was almost imperative in the years studied, reaching 6.5% and 6.4% at 4 years for the invasive and conservative groups, respectively. Meanwhile, MI was more common among invasive patients in the first 2 years, then more common among patients in the conservative treatment group at follow-up, but ultimately the incidence was not significantly different between the groups. All other secondary endpoints were also neutral.
Get COURAGE With ISCHEMIA
The ISCHEMIA test is designed to answer key questions left over from the COURAGE 2007 test, which found no benefit from revascularization over OMT in stable CAD. At the launch of ISCHEMIA in 2011, Hohman himself acknowledged that the medical community was "very difficult to accept [COURAGE]."
Some have rejected the findings, noting that COURAGE uses outdated technology (mostly bare) metal stents) or does not really optimize patients for the best available drugs. Others cited the fact that patients were randomized after angiography, potentially altering the results; there were significant cross-links and some feared that the trial did not really include patients with the most severe ischemia. In-depth COURAGE analyzes have suggested that patients with the most ischemia appear to benefit more from revascularization.
But despite the unknown, ISCHEMIA researchers have been fighting for years to persuade doctors to admit patients. Maron known performed a song modeled on on Elvis Presley's hit, uploaded to YouTube to get people to enroll one patient that evening. The trial process was also enchanted, causing controversy to collect numbers: the primary endpoint was extended beyond cardiovascular death and MI to include resuscitated cardiac arrest, hospitalization unstable angina and hospitalization for heart failure. The researchers also chose to extend the definition of ischemia by 10% or more for nuclear perfusion imaging to include patients with 5% ischemic severity at low levels of workload (≤ 7 METS) as well as those with ECG changes during the Exercise Tolerance Test (ETT) without imaging. Most recently, the quality of life endpoint was changed to a seven-point shortened version of the Seattle Angina Questionnaire (SAQ), which was introduced after the process was funded.
These changes, to varying degrees, have provoked a challenge by experts asking whether the changes will prevent ISCHEMIA from answering key questions that hit this field after COURAGE.
But now, with these results in hand, the cardiology community must accept that ISCHEMIA has indeed overcome much of the problems identified with COURAGE, session moderator Elliott Antmann (Dr. Brigham and Women's Hospital, Boston, MA). , he told TCTMD.
"This is the best medical therapy we know how to deliver now, with the latest aggressive targets and the best cobalt-chrome thin-jet stents that elute very effective limus derivatives that reduce restenosis, and we we have a modern approach to CABG surgery. In this context, "he said," this is a very powerful study and it raises many questions. "
These answers should now inform decision-making and, critically, discussions with patients, Antman continued.
" For those who might say, "But i thought i knew all this from the course results and i didnt change what i was doing, "i would recommend these people to think about the OMT that was used in this test and the latest stent technology, and most new surgical approaches, "he emphasized." And if they think the COURAGE test is not enough to change their practice their technology and cat are advanced, and they think it would change COURAGE results, that's the test of that. "
Hohmann agreed, telling TCTMD:" For people without symptoms, who either never had symptoms, which is 10% of our cohort, or who had well-controlled symptoms within the previous month, which is 36% of our cohort, were of no use. So, I really can't understand why people will still recommend an invasive strategy, stenting or bypass and I think the number of these procedures will decrease e. That alone, we think, can save over $ 500 million a year, which is five times the cost of the process in 8 years. ”
Interpreting trial results
Also commenting on the TCTMD study, Gregg Stone, MD, PhD, School of Medicine (Icahah School of Medicine (Icahah) Mount Sinai, NY, NY), an ISCHEMIA researcher, stressed that the test results do not apply to patients with ACS, patients with grade III or IV angina, patients with heart failure or reduced ejection fraction or those with left major illness.
"I think this study supports either an invasive or conservative approach for patients with stable disease [who have] or no symptoms or mild symptoms that can be controlled by medication and moderate-ischemia "said Stone. "This tells you that you can safely revascularize patients with moderate or severe ischemia and they will feel significantly better if they had angina at the beginning. Then an absolutely sensible approach – probably the appropriate approach – is a conservative strategy if they really have no symptoms at first. Finally, if a patient who has angina at the beginning would prefer medical therapy, then this would also be a very reasonable approach after excluding the underlying disease, since the risk of sudden death seems extremely low and there is generally no difference in survival with early invasive versus conservative approach. "
Asked if this interpretation places too much emphasis on secondary health outcomes, rather than on endpoint core outcomes, not to mention the concerns in cardiology society that too many patients are usually treated with an invasive approach, Stone said, "The test results are the test results and what I just told you is the correct scientific interpretation of the results and how to apply them in patient care. ,,, Reducing angina and improving quality of life were significant, and in the United States we tend to pay for therapies that make people feel better. "
Feeling better or living longer is 'what patients want,' Stone continued. "What we showed in this trial with great precision is that we will not make you live longer by undergoing an invasive strategy, but it will most likely make you feel better. And with a relatively small number of patients needed for treatment to make you have angina. I think this is a significant and important finding – it was the main secondary endpoint of the process and was a completely separate study for this reason, because these are our two priorities. “
Sanjay Cowl, Ph.D. (Cedars-Sinai Medical Center, Los Angeles, CA), which also reviewed TCTMD test results, gave researchers an "A +" on ISCHEMIA's design and behavior, adding that "data quality is excellent."  Otherwise, "nothing surprised me. I think the lack of death or benefit of MI is in line with previous evidence and the improved incidence of angina is also in line with previous evidence. "The catch," Cowl continued, "is that the functional result was a secondary endpoint, and so the key question is how to interpret a favorable secondary endpoint when the trial fails to win the main endpoint?"
And the answer is: doomed. In general, you cannot make any meaningful conclusions, but this is a statistical sign. The fact that an invasive strategy has the advantage of reducing angina is consistent with preliminary evidence. ,,, These results may be disappointing for some, but not surprising to me. "
Asked about the problem of interpreting secondary health outcomes, Hochman had to say," This is not a new drug [for which] we seek approval from the FDA, where you live and die from your primary endpoint and whether it reaches "statistical significance." We specifically tried to see what the hazard ratio – point estimate – was for multiple endpoints, with precision around those endpoints. So, for example, stroke is very important for patients and we have shown that stroke rate is very low and similar between the two groups. You don't look at it the same way you look at the drug registration test and clinical events are important for patients, especially survival, and quality of life is also important. "
Spertus emphasized the same thing in his presentation today. "Patients with angina should have shared decision-making to align their treatment with the patient's goals and preferences," he said.
But speaking to TCTMD last month, Spertus predicts that Medicare and payers will pay close attention to the results of ISCHEMIA.
Antman, asked if he expected changes in the refund after ISCHEMIA, replied that it was "too soon to say."
"There are many more things we need to know, detailed analyzes and a document that has not yet been submitted – we will all want to read this book," he commented and added: "We will to ask questions in detail such as – tell me how it was in the "ideal" groups, those who received complete revascularization compared to those who actually achieved LDL below 70 mg / dL and BP below 130 mm Hg in the conservative group. a very important thing. "
Even more important will be longer-term insights," Antman continued. you know that you are a patient or your relative is a patient with stable angina pectoris. The question is not “what do I get in the next 4 years?” but “in the next 10, 15 or 20 years [what happens] if I continue with a conservative approach or early an invasive approach? And I hope investigators manage to get the funding to do that, because that's what we really want to know. "
" Big win for CT "
One group of cardiologists who can mark the results of ISCHEMIA tonight are supporters. CT angiography, which indicated the 434 patients excluded from the study based on CT findings showing major left disease. as 1218 patients were excluded due to lack of obstructive CAD despite symptoms of chest pain.
Commenting on the results for TCTMD, Dr. Jonathan Leipsic ((St. Paul Hospital, Vancouver, Canada) "Big Profit for CT."
"Stress the real-world test does not confidently identify epicardial coronary artery disease, "he says." [Cardiac] CTA serves as a good lab gatekeeper with a cathode of more than 85% of participants screened for CT, revascularized, emphasizing that CTA is required before conservative initial management. to confirm the extent of the disease and to exclude [left main] disease. Maybe then all that is necessary одимо, е специфична за лезията физиологична оценка, за да се прецени кои лезии се нуждаят от реваскуларизация въз основа на последните данни като FAME 2 и SWEDEHEART. Този подход в действителност може да доведе до още по-дълбоко облекчаване на стенокардия и намаляване на MI в интервенционната рама. ”
Дъглас направи подобна точка, отбелязвайки :„ Над една трета от населението на пациентите бяха неуспешни екрани и затова единственият начин да се знае за тях [cases]. , , е от КТ. Не съм сигурен, че повечето от нас са готови да поемат 5% риск да не се намесят в лявата главна. Ако трябва да действате на ISCHEMIA и да кажете: „Ще лекувам всичките си пациенти с медицинско управление и ще се намеся, ако стенокардията им не изчезне или тя се ускори или не могат да управляват лекарствата си“, тогава [you risk missing] 5% от онези пациенти в тази популация, които са напуснали основното заболяване, и знаем, че реваскуларизацията е животоспасяваща при тези хора. Не бих се чувствал удобно като лекар с пациент със значителна исхемия, просто приемайки, че няма ляво основно заболяване в тази популация. Това казва, че трябва да направите някакъв втори ангиографски тест, или да използвате CT или просто да отидете в катодна лаборатория за преглед. “