Whenever you order a test, it is essential to know what you are going to do with the results. Tests, by themselves, cannot improve patient outcomes. Benefit can only occur if the test results in appropriate patients receiving a proven intervention.
With stress testing, we are often hoping for negative results so we can give our patients the “all clear”. Unfortunately, as was discussed in the last post, the test is nowhere near sensitive enough to provide that level of reassurance. (Luckily, as was discussed in part 1, our patients are so low risk when stress tests are ordered, we end up being right accidentally.) This post focuses on what happens when a stress test is positive. In other words, once you find the “high risk” patients, what can you do to help them?
Really, that means that we are talking about angiography and stenting, because that is the direct result of positive stress tests. (Poldermans 2006; Young 2009) (A conversation about medical management is worthwhile, but is usually based on risk factors rather than stress test results.) Percutaneous intervention clearly has a role in STEMI patients, but what are the outcomes of invasive testing and interventions in less sick ACS patients?
- This post is part of a series exploring the practice of stress testing.
NSTEMI and Unstable Angina
Realistically, we should limit our discussion to low risk patients with normal ECGs and negative troponins, because that is the group of patients that we send for stress tests. However, for some context, let’s start by looking at the use of an invasive strategy in the management of patients with NSTEMI and unstable angina.
Fanning JP, Nyong J, Scott IA, Aroney CN, Walters DL. Routine invasive strategies versus selective invasive strategies for unstable angina and non-ST elevation myocardial infarction in the stent era. The Cochrane database of systematic reviews. 2016.
Methods: This Cochrane meta-analysis included RCTs comparing routine invasive strategies to conservative or selective invasive strategies in patients with unstable angina or NSTEMI. They found 8 RCTs including 8915 patients. None of these trials were blinded, so are all at high risk of bias. The patients in these studies were fairly clearly ACS patients. (In other words, this is not really the patient population we are stress testing.) Inclusion criteria included one of the following:
- New ST depression.
- Transient (< 20 minute) ST elevation.
- Ischaemic T-wave inversion or T-wave inversion in at least two contiguous leads.
- Elevated levels of cardiac markers.
- Coronary artery disease (CAD), as determined by a history of catheterisation, revascularisation, or acute coronary syndromes (ACS).
Results: There was no change in all cause mortality (4.2% vs 3.6%; RR 0.87, 95% CI 0.64 to 1.18). Death during the index visit was higher in the invasive treatment group (1.4% vs 0.9%, RR 1.54, 95% CI 1.02 to 2.34), but was unchanged at all other time frames. MI was also statistically unchanged during the 6-12 month follow-up period (7.8 vs 6.2%, RR 0.79, 95% CI 0.63 to 1). This 95% confidence interval touches but doesn’t cross 1, which causes great debate among statisticians when discussing what “statistically significant” means. There was a statistically significant decrease in refractory angina (33% vs 21%; RR 0.64, 95% CI 0.52-0.79) and rehospitalization (29% vs 22%; RR 0.77, 95% CI 0.63-0.94). Both of these outcomes are subjective (refractory angina was never actually defined in this document) and need to be interpreted with significant caution considering that none of the trials were blinded. (For example, when a patient presents to the emergency department 1 month later with recurrent chest pain, if they had a negative angiogram during their last visit it is highly likely that they will be sent home. On the other hand, if they were treated conservatively last time, they might be admitted to hospital this visit. Therefore, the lacking of blinding leads to increased rehospitalization in the conservative group, but it isn’t clear that this rehospitalization is a bad outcome or even necessary.) Harms are increased with the invasive strategy. Bleeding increases from 4% to 7% (RR 1.73, 95% CI 1.3 – 2.3). Procedure induced MI increases from 3% to 6% (RR 1.87, 95% CI 1.47 – 2.37). Other harms were not reported on, such as mechanical complications or potential harms from contrast (if they exist).
One major caveat is that a reasonable number of patients in the conservative groups ended up getting revascularization, so the difference in invasive management between the groups was only about 30% (absolute).
Bottom line: It isn’t clear if routine invasive management helps patients with NSTEMI and unstable angina. Invasive management clearly does not decrease the most important, objective outcome of death. There may be decreases in refractory angina and rehospitalization, but the lacking of blinding makes interpretation of such subjective outcomes tenuous. There is a small but important increase in harms such as bleeding and procedural MI using an invasive strategy. (Of course, there are definitely patients without ST elevation who need emergent activation of the cath lab. However, for the average NSTEMI patient, the benefit is marginal.)
How does this help us when we are considering stress testing? This study did not include patients we would stress test. We stress test a much lower risk population. These results demonstrate the biggest possible benefit from stress testing, not the actual benefit. If you happened to miss a patient with a NSTEMI, but the stress test caught him, you wouldn’t have saved his life by getting him to the cath lab. You wouldn’t have prevented refractory angina (because you wouldn’t have missed the symptoms). So the best possible benefit is a decrease in hospitalization, and maybe a non-statistically significant decrease in non-fatal MI, balance by an increase in bleeding and periprocedural MI. (Assuming you are having most chest pain patients follow up with primary care to consider risk factor modification and possible medical management.)
Hoenig MR, Aroney CN, Scott IA. Early invasive versus conservative strategies for unstable angina and non-ST elevation myocardial infarction in the stent era. Cochrane Database Syst Rev. 2010;(3)CD004815. PMID: 20238333
I include this older version of the Cochrane review because it contains an interesting subgroup analysis that isn’t present in the newer document. Again, there is no change in morality. However, in patients with positive troponins, there is a small benefit in preventing future MIs. In patients with negative troponins, there is increased mortality with the invasive strategy. This is potentially very important when considering stress testing, because we only send patients with negative troponins for stress tests.
PCI in stable coronary artery disease
There may be a marginal benefit to invasive intervention in NSTEMI patients, but those are not patients we send for stress tests. Patients who we are considering for discharge (or observation in certain settings) are by definition low risk. They will be symptom free, with normal or non-specific ECGs, and negative biomarkers. In other words, what we are hoping to find with a stress test is stable coronary artery disease. So does PCI help patients with coronary artery disease?
Stergiopoulos K, Brown DL. Initial coronary stent implantation with medical therapy vs medical therapy alone for stable coronary artery disease: meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172:(4)312-9. PMID: 22371919
This is a meta-analysis of 8 RCTs (7229 patients) comparing invasive management with medical therapy for stable coronary artery disease. There was no difference in mortality (OR 0.98; 95% CI 0.84-1.16). There was no difference in non-fatal MI (OR 1.12; 95% CI 0.93 – 1.34). There was no difference in unplanned revascularization (OR 0.78; 95% CI 0.57-1.06). There was no difference in persistent angina (OR 0.80; 95% CI 0.60-1.05).
Khan SU, Singh M, Lone AN, et al. Meta-analysis of long-term outcomes of percutaneous coronary intervention versus medical therapy in stable coronary artery disease. European journal of preventive cardiology. 2018; PMID: 30226394
This is a systematic review from 2018 published as a research letter. The search results in basically the exact same studies and the exact same results as the Stergiopoulos paper. (Ie, there are no major studies added since 2012, except the ORBITA study, discussed next.)
One of the problems with the prior studies of invasive management of stable coronary artery artery disease was that studies weren’t blinded. This isn’t as big a deal for objective outcomes, such as mortality (which has always been negative in these trials). On the other hand, there has been some debate about whether stents might decrease persistent angina or improve exercise tolerance, but those are subjective outcomes more prone to bias. That is why the ORBITA trial, a double-blind RCT, was so important.
Al-Lamee R, Thompson D, Dehbi HM, et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet (London, England). 2018; 391(10115):31-40. PMID: 29103656
This is a multicenter, randomized, double blind trial with sham control. They studied adult patients with angina and at least one angiographically proven lesion >70% in a single vessel. They excluded multi-vessel disease and acute coronary syndrome, among a number of other exclusions. All patients had the medical management of their angina maximized prior to randomization. All patients underwent an angiogram, with various measurements, and they were randomized while they were on the table. 105 patients had a drug-eluting stent placed and 95 were assigned to the placebo group. Most (69%) of the lesions were in the left anterior descending artery, and the mean stenosis was 85%. (These were large, potentially important lesions.) No one outside of the cath lab knew which group the patient was assigned to. There were no differences between the groups. Exercise time increased marginally in both groups (28 vs 12 seconds), but the difference between the groups was neither statistically nor clinically significant. They did a number of physiologic measurements, like peak oxygen uptake and the time to 1 mm of ST depression on a stress test, and they were all the same. They did a number of angina questionnaires, and they were all the same. Quality of life was the same.
This is the only blinded trial, and it is definitively negative. It doesn’t look at hard outcomes, but we already knew that stents don’t reduce mortality or future MIs in stable coronary artery disease. This is clearly the best evidence we have to date, and it demonstrates that stents also don’t improve any subjective outcomes in stable coronary artery disease. There is no benefit.
None of these studies specifically addresses the question that we want to ask: does identifying “high risk” chest pain patients with a stress test after emergency department work-up, and then referring those patients for invasive investigation and management, help those patients? However, the answer seems pretty clear. Outside of STEMI (or more correctly, acute occlusal MI, because not every acute coronary occlusion has ST elevation) there does not seem to be any significant benefit to invasive interventions. In NSTEMI patients, there may be a small benefit in subjective outcomes, but it is closely balanced by harms. In the low risk patients who we are sending for stress tests, it seems pretty clear that invasive management is not beneficial, but does expose patients to harms. Therefore, assuming that you are going to have patients follow up with primary care for risk factor modification and medical management no matter what, there doesn’t seem to be any mechanism through which stress testing could possibly help.
Poldermans D, Bax JJ, Schouten O, et al. Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate-risk patients receiving beta-blocker therapy with tight heart rate control? Journal of the American College of Cardiology. 2006; 48(5):964-9. PMID: 16949487
Young LH, Wackers FJ, Chyun DA, et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA. 2009;301:(15)1547-55. PMID: 19366774