Clinical Trial Update: Rapid Communication

Insights From the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) Trial

Cath Lab Digest talks with Kirk N. Garratt, MSc, MD, MSCAI, Past President Society for Cardiovascular Angiography and Interventions (SCAI); John H. Ammon Chair of Cardiology and Medical Director, Center for Heart & Vascular Health, Christiana Care Health System, Wilmington, Delaware.

Cath Lab Digest talks with Kirk N. Garratt, MSc, MD, MSCAI, Past President Society for Cardiovascular Angiography and Interventions (SCAI); John H. Ammon Chair of Cardiology and Medical Director, Center for Heart & Vascular Health, Christiana Care Health System, Wilmington, Delaware.

The ISCHEMIA trial results were presented November 16, 2019 at the American Heart Association’s 2019 Scientific Sessions.1,2

 

What is your initial reaction to the ISCHEMIA trial results?

ISCHEMIA showed that the use of revascularization with either stents or a bypass operation doesn’t need to be the first step in the management of stable patients with moderate or severe ischemia and mild or moderate symptoms. Instead, we can rely on medical therapies for a period of time, and when medications are no longer sufficient, we can lean on more invasive treatment measures. In fact, this has been a standard approach in the care of stable ischemic patients for some time. It has been many years since we believed that a stent would prevent stable patients from dying suddenly or developing heart failure. We’ve learned that a bedrock of appropriate medications is the essential element in preventing serious adverse events. One of the surprises that came out of the main ISCHEMIA trial was the finding that spontaneous heart attack rates were lower for patients who underwent early invasive care over about four years of follow-up. That finding is going to require more study to understand fully; it is slightly different than what we have seen in the past. The FAME II study3 did find a lower rate of unstable symptoms and heart attacks with early invasive care, but other studies didn’t identify this benefit. The other important piece to take away is that the quality of life assessments in ISCHEMIA confirmed what we have long believed to be true: revascularization offers a consistent improvement in quality of life for patients with stable ischemic heart disease. We have offered revascularization to this patient population for more than decade primarily to improve their ability to tolerate activities without limiting chest pain or other symptoms. The ISCHEMIA study confirmed that improvement in quality of life is a reliable benefit when stents are placed or patients undergo bypass operations.

I am disappointed that early media coverage of the ISCHEMIA trial has suggested that this study somehow suggests we are being wasteful with our use of revascularization techniques today. I have read written reports claiming that ISCHEMIA has identified wasteful spending in healthcare in America, finding that doctors put stents in patients who have no chest pain, and that it is costing us hundreds of millions of dollars fruitlessly. That simply is a misrepresentation of the facts of the study. ISCHEMIA found that offering stents or bypass surgery to patients with even mild or moderate symptoms is appropriate. The only patients who didn’t benefit were those who had no symptoms. This shouldn’t be a surprise, since it’s hard to make someone with no angina have less of it. For everyone else, symptoms were reduced, function was improved and quality of life was enhanced. Far from being a wasteful treatment, revascularization offers great value to stable patients, delivering exactly what they hope to get from their doctors when they have anginal symptoms.

 

Will ISCHEMIA affect shared decision making in terms of how physicians present the option of revascularization to patients?

We in the Society for Cardiovascular Angiography and Interventions (SCAI) believe that all care decisions need to be made jointly with well-informed patients and their families. A key question now is this: what will be discussed in these conversations? Will doctors tell patients they might have lower risk of spontaneous heart attack in the future if they have invasive therapy? Before ISCHEMIA, I would have said that prudent, conservative interventionalists would steer away from saying that, because we didn’t have a solid basis for defending that claim. ISCHEMIA suggests this might be a possible benefit. Again, we haven’t heard the full story. I haven’t seen any of the data other than the slides that were presented. I agree with the ISCHEMIA authors that further evaluation of the data, and perhaps longer follow-up, will be necessary to fully understand the implications of this observation. But as it stands today, cardiologists must consider a reduction in spontaneous heart attacks as a possible benefit of invasive care. At a minimum, ISCHEMIA reassures interventional cardiologists that patients should be able to get right back to playing with their grandkids or playing 18 holes of golf without limiting symptoms. We can now make this point with greater conviction and help patients to make a positive, informed decision about their heart care.

 

How should physicians evaluate the option of medical therapy considering the support that patients receive in a clinical trial versus what might be more common in daily life?

The challenge with medical therapies is getting patients to adhere to medications that we know are effective, but are cumbersome and interfere with the flow of daily life. Prior studies have shown that even life-sustaining medications are often abandoned just a few months after they are prescribed. At a year after a heart attack, for example, as few as a third of the patients who are prescribed these medications are still taking them regularly. So that’s always a challenge in a clinical environment. In the context of a clinical trial, there are greater resources to help provide medications and remind patients of the importance of taking them. I think many patients feel that after having a bypass operation or a stent they won’t have to take as many pills. Well, in ISCHEMIA, aspirin, beta blockers, and calcium channel blockers were all used at similar rates in the conservative and invasive groups. Dual antiplatelet therapy was used more in the invasive group, and other anti-anginal medications were used more in the conservative group, as expected. So we shouldn’t tell patients that stents will free them from their pills, but rather we should encourage compliance with medical therapies even after revascularization.  From the position of SCAI, we completely agree that invasive therapy needs to occur on a foundation of good medications. The fact that patients are challenged taking their pills doesn’t mean we can simply ignore our responsibility to help them be compliant. Invasive therapies may help you sustain the quality of life you are seeking with fewer anti-anginal pills, but having a stent or bypass operation doesn’t mean your medications are no longer important.

 

Did the patients randomized to early medical therapy have a more complex medication regimen?

We need to look at the data more closely to figure that out. In the conservative group, the intent was to push medical therapies to the limit of tolerance in an effort to get complete control of their symptoms of ischemia. We do know that patients in the conservative arm were twice as likely to have a high level of medical optimization as the invasive arm. I would expect patients in the conservative arm were taking more medications each day and taking larger doses of each type of medication. In terms of complexity, remember that three-quarters of patients in the invasive arm were treated with stents, and all of those subjects were advised to take dual antiplatelet therapy (DAPT) for at least six months. The data shown at AHA confirmed that DAPT was much more prevalent in the invasive group compared with the conservative group, as expected. Even after 12 months, when stent recipients would have been told they can stop, there was a difference in the use of DAPT between these two treatment groups, although the difference narrowed quite a bit after 18 months. DAPT has its own issues, so use of DAPT may have increased the complexity of the medical program for the invasive care group. It is a complex situation and we’ll need an opportunity to look at the data more thoroughly.

 

Do you think that medical therapy might in the future prove superior to intervention in this group of patients?

I think this kind of question allows the conversation to slip sideways to a certain degree. The lay press finds it easier to think of this as “stents vs medicine.” But as I’ve said, it is a much more complex and nuanced conversation that we need to have. The ISCHEMIA trial wasn’t designed to pit one treatment against another. It was designed to help us understand how to best integrate care options to arrive at best outcomes. Does a very intense medical program provide benefits that are superior, equivalent, or inferior to less intense medications and early use of revascularization in stable patients with mild or moderate symptoms and moderate to severe ischemia? We learned that intensified medical therapies can keep people safe, but they don’t allow patients to enjoy the same quality of life as they can get if they pursue an early invasive care plan. That is not really pitting one group against another. It is bringing a better understanding of how to use invasive care best.

 

You mentioned the FAME II trial. Did ISCHEMIA consider whether any adjunctive technologies were used when stents were placed?

Fractional flow reserve (FFR) data were collected on some patients that underwent invasive care and were used to confirm that lesions undergoing invasive treatment were in fact ischemia producing. FFR was recommended if a targeted lesion appeared to narrow a vessel by less than 80%, or if an apparently non-significant lesion leading to a myocardial bed that was ischemic on non-invasive testing was found. We haven’t yet seen presentations of those findings beyond a top-level disclosure.

 

How do you see ISCHEMIA in relation to COURAGE4?
ISCHEMIA was a good extension of the lessons from COURAGE. The interventional community was unhappy about COURAGE, mostly because there was concern that the stable patients most likely to derive benefit from invasive care, those with the most severe disease, might have been excluded from randomization by concerned doctors and patients. ISCHEMIA showed that we don’t have to worry about an increased risk of death, cardiac arrest or heart failure if we start with intensified medications. It also proved that early invasive care will reliably provide a better quality of life than intensified medical therapies, and might lower the risk of spontaneous heart attacks. Frankly, I believe the interventional community was more unhappy about the media coverage of COURAGE than the actual results of the trial. Most academic interventionalists were prepared to hear that early invasive care does not affect rates of hard events very much, because the work that came before COURAGE had suggested that was the case. It seemed that the lay media wanted to distill a complex story into a simple one, and that took the form of “stents vs medicines,” with medicines the “winner.” Because of this, a lot of people pointed at the deficiencies of the COURAGE trial. The ISCHEMIA trial was designed specifically to address many of those concerns. By allowing randomization of patients without knowledge of their coronary anatomy, a big concern about selection bias in COURAGE was avoided. So in that regard, ISCHEMIA is a terrific extension of COURAGE. I’m disappointed that early media reports about ISCHEMIA are proving to be just as over-simplified and misleading as the reports about COURAGE. Far from showing that revascularization, and especially stents, are unnecessary and wasteful, ISCHEMIA clarifies the value of invasive care when used optimally.

 

What about any presented or forthcoming substudies5?

The ISCHEMIA Chronic Kidney Disease (CKD) substudy was quite interesting and somewhat of a disappointment for the interventionalists, I think. Patients with CKD are at high risk for adverse events. Certainly, risk for procedural complications is higher, but they are also at very substantially greater risk of death, stroke and spontaneous heart attack compared to patients without CKD. There was the hope that aggressive care using invasive therapies early might provide CKD patients additional benefits, but unfortunately that was not found in this substudy. It was a smaller substudy and didn’t have the power of the larger ISCHEMIA trial, but at this point, it unfortunately looks like even aggressive care with early use of invasive treatments doesn’t provide as much benefit for these at-risk patients as one would hope.

The other main substudy still forthcoming is the CIAO-ISCHEMIA, focusing on changes in ischemia and angina over one year among ISCHEMIA trial screen failures with no obstructive coronary artery disease on computed tomography angiography. These patients may have microvascular disease or other myocardial problems, and current evidence suggests they are at increased risk of adverse events, so the ISCHEMIA trial authors are seizing the opportunity to look prospectively at their outcomes. Data have not yet been presented.

 

Disclosure: Dr. Garratt  reports receiving honoraria for his work on Clinical Event Adjudication Committees for the EXCEL trial (Abbott Vascular) and for the JARVIK 2000 DT trial (Jarvik Heart).  He is a founder and equity holder in LifeCuff Technologies, Inc.

 

Dr. Garratt can be contacted at kirk.n.garratt@christianacare.org.

 

References

  1. Hochman JS. ISCHEMIA: International study of comparative health effectiveness with medical and invasive approaches (ISCHEMIA). Primary report of clinical outcomes. Available online at https://professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_505166.pdf. Accessed November 19, 2019.
  2. ISCHEMIA trial finds no evidence of lower cardiac event rates in patients treated with heart procedures, but better quality of life. NYU Langone Health press release. November 16, 2019. Available online at https://www.cathlabdigest.com/content/ischemia-trial-finds-no-evidence-lower-cardiac-event-rates-patients-treated-heart-procedures-better-quality-life. Accessed November 19, 2019.
  3. Xaplanteris P, Fournier S, Pijls NHJ, et al; FAME 2 Investigators. Five-year outcomes with PCI guided by fractional flow reserve. N Engl J Med. 2018 Jul 19; 379(3): 250-259. doi: 10.1056/NEJMoa1803538.
  4. Boden WE, O’Rourke RA, Teo KK, et al; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12; 356(15): 1503-1516.
  5. ISCHEMIA Trial Protocol. Available online at https://clinicaltrials.gov/ProvidedDocs/22/NCT01471522/Prot_001.pdf. Accessed November 19, 2019.