Both the "extended" endpoint and death / MI did not differ between arms, but QoL was significantly better with PCI / CABG.
PHILADELPHIA, PA (UPDATED) —After more than 10 years and $ 100 million, the International Study of Comparative Health Efficiency with Medical and Invasive Approaches (ISCHEMIA) has yielded a crucial result: an invasive strategy on The pinnacle of optimal medical therapy (OMT) offers no benefits beyond OMT alone in preventing a number of important cardiovascular events in patients with stable, moderate to severe coronary artery disease.
It voted for the ISCHEMIA study's "expanded" primary endpoint for cardiovascular disease, MI, hospitalization for unstable angina, hospitalization for heart failure, or resuscitation due to cardiac arrest ̵
Where angiography followed by PCI or CABG had the edge over medical treatment in this highly anticipated study, angina was relief. Among subjects with daily or weekly angina, half of the invasively treated patients were angina-free at 1 year, compared to only 20% in the OMT group.
“What do patients care about when seeking treatment? They care about living longer and feeling better, says study director Judith Hochman, MD (NYU Langone Medical Center, New York, NY), to TCTMD. "In median 3.3 years of follow-up – and up to 5 years – overall, there was no difference in their survival in this study, but they felt better with the invasive strategy if they had angina at baseline. So this is really a perfect example of where we need to make shared decisions between patients and their physicians. ”
Hochman, who led the study with primary researcher David J. Maron, MD (Stanford University School of Medicine, CA), presented the main findings here today at American Heart Association 2019 Scientific Sessions Today; Life Quality Results (QoL) were presented by John Spertus, MD (Saint Luke & # 39; s Mid America Heart Institute, Kansas City, MO). Sripal Bangalore, MD (NYU Langone Medical Center) presented the associated The ISCHEMIA-CKD study results, followed by the QoL analyzes for this predetermined ISCHEMIA study, and, like the main results, the ISCHEMIA-CKD found no benefit with an invasive approach over OMT in a population of patients with advanced chronic kidney disease and significant, stable coronary disease.
All the experts who spoke to TCTMD said that they were not particularly surprised by the results, but all had warnings.
Pamela Douglas, MD (Duke University School of Medicine, Durham, NC) joked that despite what people say: "Everything ISCHEMIA found would have been a bit of a surprise because there really is equipment on it, with people who feel "in their legs" about one or the other. " That being said, she continued, it is not "Horrible" a surprise that there were no differences in the main results, nor that there were multiple events early in the invasive group that were then matched by later events in the conservative arm – details that were also presented by Hochman in her presentation today.  ISCHEMIA final
ISCHEMIA, performed at 320 sites in 37 countries, registered 5,179 patients with stable CAD, preserved ejection fraction and moderate to severe ischemia based on either stress imaging or exercise tolerance test (ETT). In total, more than 50% of patients in the trial had severe inducible ischemia at baseline, 33% had moderate and 12% had mild.
I would think that the number of these procedures would decrease. That in itself, we estimate being able to save over $ 500 million a year, which is five times the cost of the trial over 8 years. Judith Hochman
Patients were randomized to a strategy for invasive coronary angiography followed by revascularization, if necessary, on top of OMT or to an initial conservative strategy of OMT alone. Randomization was performed before angiography and blind blind CT angiography (CTA) was performed in approximately two-thirds of the enrolled patient cohort to rule out life-threatening left primary disease (or disease considered comparable severity) and other acute problems such as aortic dissection. or, in a smaller proportion of patients, to confirm that CAD was actually present. Ultimately, 73% of the randomized subjects had a CTA study.
At a median of 3.3 years (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 (adjusted HR 0.93; 95% CI 0.80-1.08). Event curves beyond 5 years show that the conservative strategy had fewer CV events occurring in the first 2 years, while the invasive strategy held the edge between years 3 and 5. The absolute difference between the groups in both periods was about the same, which led to similar results at final follow-up. Investigators hope to receive funding to continue to follow patients for another 5 years.
For the main secondary endpoint of CV death or MI, the event curves followed a similar pattern, crossing the 2-year mark, but again did not differ significantly after 4 years: 13.9% in the conservative group versus 11.7 % in the invasive group (HR 0.90; 95% CI 0.77-1.06).
Rates of death for all causes were almost overlapping over the years studied, reaching 6.5% and 6.4% after 4 years for the invasive and conservative groups, respectively. However, MIs were more common among the invasively treated subjects for the first 2 years, and then more frequently among the conservative therapy groups in subsequent follow-up, but ultimately the frequency did not differ significantly between the groups. All other secondary endpoints were also neutral.
Take COURAGE With ISCHEMIA
The ISCHEMIA trial was designed to answer key questions left over from the 2007 COURAGE study, which found no benefit of revascularization over OMT in stable CAD. At the time of ISCHEMIA's launch in 2011, Hochman himself acknowledged that the medical community had been "very difficult to accept the [COURAGE] results."
Some refuted the findings, noting that COURAGE used outdated stent technology (mostly only) metal stents) or did not optimize patients on the best available medication. Others pointed to the fact that patients were randomized after angiography and could potentially skew the results; there were significant transitions, and some feared that the trial did not really register patients with the most severe ischemia. In-depth analyzes of COURAGE suggested that patients with the most ischemia appeared to have greater benefit from revascularization.
But despite the unknown, ISCHEMIA investigators struggled for years to convince doctors to enroll patients. Maron performed a song that was modeled on an Elvis Presley hit, uploaded to YouTube, to comfort people registering a patient just that night. The lawsuit was also postponed, prompting controversy to throw up the numbers: The primary endpoint was extended beyond cardiovascular death and MI to include resuscitated cardiac arrest, hospitalization for unstable angina and hospitalization for heart failure. The researchers also chose to extend the definition of ischemia from 10% or more on nuclear perfusion imaging to include patients with 5% ischemic load at low exertion levels (≤ 7 METS) as well as with ECG changes during exercise tolerance testing (ETT) without imaging. Most recently, the quality of life endpoint was changed to the abbreviated version of Seven Points by the Seattle Angina Questionnaire (SAQ) which was introduced after the trial was funded.
These changes, to varying degrees, prompted a shout from experts who asked whether the changes would prevent ISCHEMIA from answering key questions that have plagued this field since COURAGE.
But now, with these results in hand, the cardiology community should accept that ISCHEMIA actually overcame many of the problems identified with COURAGE, Session Moderator Elliott Antman, MD (Brigham and Women & # 39; s Hospital, Boston, MA) told TCTMD.
“This is the very best medical therapy we know how to deliver now, with the latest aggressive goals. , and the very best cobalt chrome-thin-stents that elute very effective limus derivatives that reduce restenosis, and we have a modern approach to CABG surgery. In that context, he said, "this is a very powerful study and it answers many questions."
These answers should now inform decisions and critically, discussions with patients, Antman continued.
"To those who can say: & # 39; But I thought I knew about all this from the results of COURAGE, and I have not changed what I do, & # 39; I recommend that these people think of the OMT that was distributed in this trial, and the very latest stenting technology, and the very latest surgical approaches, "he emphasized." And if they thought the COURAGE trial was not enough to change practice because their technology and laboratory had advanced and they felt it would have changed the results of COURAGE, this is the test of it. "
Hochman agreed and said to TCTMD:" For people without symptoms, who either have never had symptoms, which were 10% of our age, or had well-controlled symptoms during the previous month, which was 36% of the year, were no benefit, so I really don't see why people would still recommend an invasive strategy, stenting or bypass surgery, and I would think that the number of these procedures would decrease. That in itself we estimate could save over $ 500 million a year, which is five times the cost of the trial over 8 years. ”
Interpretation of test results
Also a comment on the study for TCTMD, Gregg Stone, MD (Icahn School of Medicine at Mount Sinai, New York, NY), an ISCHEMIA investigator, stressed that the study 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 main disease.
"I believe this study supports either an invasive or a conservative approach for patients with stable disease [who have] neither symptoms nor mild symptoms that can be controlled with medication and moderate to severe ischemia," Sa Stone "It tells you that you can safely revascularize patients with moderate or severe ischemia and that they will feel significantly better if they had baseline angina. Then a perfectly sensible approach – probably the right approach – is the conservative strategy if they really have no symptoms at the outset. And finally, if a patient with baseline angina prefers medical therapy, it would also be a very reasonable approach once the left disease is excluded, because the risk of sudden death appears to be extremely low and overall there is no difference in survival with an early invasive versus a conservative approach. "
Asked if this interpretation put too much emphasis on secondary health outcomes rather than primary endpoint findings, not to mention the concerns in cardiology Stone said that too many patients are usually treated with an invasive approach," Stone: "The test results are the study results, and what I just told you is the correct scientific interpretation of the results and how to apply them to patient care … The reductions in angina and the improvement in quality of life were significant, and in the US we have tended to pay for treatments that make people feel better. "
Feeling better or living longer is" what patients want, "Stone continued." What we have shown in this trial, with High precision is that we will not make you live longer by undergoing an invasive strategy, but we will probably make you feel better. And with a relatively small number of patients needed to treat to get rid of angina. I think it is a significant and important finding – it was the most important secondary endpoint of the trial, and it was a very separate study done for that reason because it is our two priorities. "
Sanjay Kaul, MD (Cedars-Sinai Medical Center, Los Angeles, CA), who also reviewed the test results for TCTMD, gave the investigators an" A + "for ISCHEMIA's design and behavior, and added that "the quality of the data is excellent."  Otherwise, he continued, "nothing surprised me. I think the lack of a death or MI benefit is consistent with previous evidence and the improved frequency of no angina is also consistent with previous evidence. "
" The catch, "Kaul continued," is that the functional outcome was a secondary endpoint, and so the most important question is, how do you interpret a favorable secondary endpoint when the attempt does not win at the primary endpoint? "And the answer is: with caution. Initially, you can't draw any meaningful conclusions, but it's a statistical caveat. The invasive strategy had the advantage of reducing angina consistent with previous evidence … These results can be disappointing. to some, but they are not surprising to me. "
When asked about the problem of interpreting secondary health outcomes, Hochman had this to say:" This is not a new drug [for which] We are seeking approval from the FDA, where you live and die from the primary endpoint and whether it reaches & # 39; statistical significance. & # 39; We specifically decided to see what the hazard ratio – the score estimate – was for multiple endpoints, d precision around these end points. So, for example, stroke is very important for patients, and we showed that stroke rate was very low and equal between two groups. You do not look at this in the same way you look at a drug registration course, and clinical events are important for patients, especially survival, and quality of life is also important. ”
Spertus emphasized the same in his presentation today. "In patients with angina, shared decision-making should be done to align treatment with patients' goals and preferences," he emphasized.
But while talking to TCTMD last month, Spertus predicted that Medicare and payers will closely monitor ISCHEMIA's results.
Antman, when asked if he expected changes in reimbursement after ISCHEMIA, said it was "too soon to say."
"There are many more things we need to know, detailed analysis and the paper that has not been submitted yet – we will all want to read that paper," he commented, adding, " We will ask detailed questions like – tell me what it was like in the & # 39; ideal & # 39; groups, those who got complete revascularization against those who really achieved a LDL below 70 mg / dL and a BP below 130 mm Hg in it conservative group. It's going to be a very important thing. "
Even more important will be insight in the longer term, Antman continued." Imagine you are a patient or a relative to you, a patient with stable exertion angina. The question is not 'what brings me to the next 4 years?', but 'over the next 10, 15 or 20 years, [what happens] if I go with a conservative approach or a early invasive approach? And I hope investigators succeed in getting mine to do it, because that's what we really want to know. "
& # 39; A great win for CT & # 39;
A group of cardiologists who may be celebrating ISCHEMIA results tonight are advocates for CT angiography, which also points to 434 patients excluded from the trial on the basis of CT findings showing left main disease. such as the 1,218 patients excluded for having no obstructive CAD despite chest pain symptoms.
Comment on the results of TCTMD, Jonathon Leipsic, MD ((St. Paul & # 39; s Hospital, Vancouver, Canada)), called the study "A Great Gain for CT."
"Stress testing in the real world does not identify with epicardial coronary disease," he said. "[Cardiac] CTA served as a good gatekeeper to the cath lab with over 85% of participants screened at CT who were revascularized, emphasizing that prior to conservative initial management, a CTA is needed to confirm the extent of disease and to exclude [left main] Maybe, then, all that is needed is lesion-specific physiological evaluation to assess which lesions need revascularization based on recent data such as FAME 2 and SWEDEHEART, this approach may actually lead to an even deeper angina relief and MI reduction in that intervention arm. . "
I would not be comfortable as a doctor with a patient who has significant ischemia, simply on the assumption that there was no left disease in this population. Pamela Douglas
Douglas made a similar point, noting : “Over a third of the patient population was screen failure and therefore the only way to know about diss e [cases]. is from CT. I'm not sure most of us are willing to take a 5% risk of not interfering with the left. If you were to go against ISCHEMIA and say, "I will treat all my patients with medical treatment, and I will intervene if their angina does not disappear or it accelerates or they cannot administer their medication," [you risk missing] 5% of the patients in this population who have left the main disease, and we know that revascularization is life-saving in these people. I would not be comfortable as a doctor with a patient who has significant ischemia, simply on the assumption that there was no major illness in this population. This means that you need to do some kind of angiographic second test, either using CT or just go to a cathedral to see. "
Starts the discussion
There is more work to be done in this contentious field. Both Hochman and Douglas pointed to the high proportion of patients in the trial of chest pain, but less ischemia and no identifiable obstructive disease, who are more likely to be women The current drug regimen in this group is unknown; more details may emerge from the CIAO-ISCHEMIA trial, which Douglas noted looks at individuals screened by ISCHEMI because they had no obstruction coronary disease on coronary CT angiography.
Hochman also emphasized to the TCTMD that the degree of complications in the trial was very low, partly a reflection of the strict quality control measures implemented in this trial, and therefore the results do not extend to centers with lower volume or, for that matter, for patients who are not maximized on Guideline Medical Therapy (GDMT).
Alice K. Jacobs MD (Boston Medical Center, MA), brought up at this point as the formal discussion for the trial following the main arena presentation. "Compliance with GDMT is critically important and challenging, even in the context of a randomized controlled trial and certainly in our clinical practice," she said.
Maximizing patient care, if a conservative approach is chosen, will be mandatory to achieve the same results seen in ISCHEMIA, Jacobs noted. Furthermore, “it is up to all of us as clinicians to discuss early and late risks and benefits, and what to expect based on the degree of angina. . . . The patient's point of view cannot be exaggerated. "
It is also the reality that ISCHEMIA was not a blind study, a point raised by ORBITA's principal investigator, Rasha Al – Lamee MBBS (Imperial College London, England). She pointed out that the number needed to be angina-free in ISCHEMIA was three, compared to five in ORBITA. "We need to be a little careful," she said. "It is clear that some of that effect may be the effect of placebo, and we cannot underestimate what we do as doctors when it comes to making these patients feel better."
Further discussion nulled about the trade-off of early and spontaneous MI of early periprocedural MI. Panel member Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai), called the study "practice change" for the many clinicians who quickly refer these patients for angiography. "Now we can relax – at least for the first 2 years," she said.
But a "very important question," she continued, is what she should tell the patients to explain this trade-off. "The late events make me believe wholeheartedly that we can't walk away from these patients without knowing what's next, and the follow-up to ISCHEMIA is at least as important as what we learned today."
Mehran also raised a question often asked, the possibility "we do too many stress tests on these patients who have moderate or mild symptoms… Perhaps it is more important to exclude the left head when using a CTA."
On At this point Jacobs quickly said that "I think we will still need stress tests to make the diagnosis, because angina is a diagnosis on the bedside table and not a cat lab diagnosis. So we need stress tests to do that."
But the panelist James de Lemos, MD (UT Southwestern Medical Center, Dallas, TX), took a different approach and predicted, "The effect of this for non-invasive testing is tremendously downstream … and that's where we see more of the impact on our practice because many of us as a result of Rasa's work [with ORBITA] have become more conservative, but this will have major effects on cardiac testing. "
a panelist, Brahmajee K. Nallamothu, MD (University of Michigan, Ann Arbor ), ISCHEMIA said definitively will change practices, as COURAGE did. "This teaches me that not all patients with moderate to severe ischemia need to go straight to the cath lab," he explained.
Spertus requested an investment not only in tools containing large data sets to help physicians make evidence-based decisions, but also the research to study how to implement such tools. "If we build the tools and nobody uses them," he said, "then we have wasted our time."
The last word went to Hochman, who noted that there had been a lot of talk on social media about the $ 100 million price tag for this study, which she noted is more than offset by the savings that can be obtained if stable, asymptomatic patients do not will be sent to cath lab. “I want you to know that this was not a pragmatic simple test. Everything was read by the core laboratory – ECG at baseline [and] over time, every single stress test, every [cardiac] CTA, the angiograms, the PCIs, the surgical reports; the clinical event committee judged every event. It costs money. I think it was well invested money, ”she concluded.