stable CAD: CT vs invasive angiography

 

A recent pragmatic, randomized controlled European trial compared CT angiography with invasive coronary angiography in patients with intermediate pretest probability of obstructive coronary artery disease (CAD) and stable chest pain, finding no significant difference in subsequent cardiac events but fewer major procedural complications with the CT (see cad stable CT vs invasive angio NEJM2022 in dropbox, or DOI: 10.1056/NEJMoa2200963), the DISCHARGE trial.

 

Details:

-- 3561 patients who had intermediate pretest probability of obstructive CAD and were referred to one of 26 European centers for invasive angiography (ICA), between October 2015 and April 2019

-- patients were randomized equally to CT vs ICA, with >97% adherence to the randomized assignments

-- 56% women, median age 61, 80% were outpatient at the time of enrollment, 99% white, 41% employed/40% retired/2% disabled

-- chest pain: typical angina 14%/atypical angina 46%/non-anginal chest pain 37%

-- median pretest probability of obstructive CAD: 38%

-- meds at a median of 1 year: statins 54%, antiplatelet 48%, b-blocker 42%, nitrates 8%, ca blockers 23%, ACE/ARB: 49%

-- reasons for invasive coronary angiography (ICA) referral: 

    -- patients felt to be at high cardiovascular risk with inadequate response to medical therapy: 47% (high cardiovascular risk usually means either lots of myocardium at risk (eg left main disease) or significant left ventricular dysfunction)

    -- severe angina with inadequate response to medical therapy: 20%

    -- intermediate pretest probability without typical angina after functional testing (stress tests) showing ischemia: 16%

    -- lower intermediate risk with inadequate response to medical treatment: 10%

    -- intermediate pretest probability without typical angina after nondiagnostic functional testing: 3%

-- comorbidities: hypertension 60%/diabetes 15%/hyperlipidemia 48%

-- functional test performed before intervention: 34%, with positive results in 15% and negative results in 15%

-- quality of life indicators: EQ-5D visual analog scale score = 67, SF-12v2 physical component summary = 44; both groups were similar at baseline

-- both groups were advised about risk factor modification and secondary prevention

-- exclusion criteria included being on hemodialysis, not being in sinus rhythm and not being pregnant

-- follow-up of 3.5 years (2.9-4.2 yrs)

 

-- primary outcome: major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke)

-- secondary outcomes: procedure-related complications and angina pectoris

 

Results:

-- participants with >50% obstructive CAD found on CT who also underwent ICA (n=386 of the 1808), on ICA had: 44% had obstructive CAD (>50%, with high-risk anatomy); 35% obstructive CAD (>50%, without high-risk anatomy); 16% nonobstructive CAD; 5% no CAD [ie, those with abnormal CTs had a very high likelihood of significant CAD on ICA, suggesting high sensitivity for the CT]

 

-- major adverse cardiovascular events (MACE) on followup:

    -- CT: 38 of 1808 patients (2.1%)

    -- ICA: 52 of 1753 patients (3.0%)

        -- HR 0.70 (0.46-1.07), not statistically significant 30% decrease in a strong trend to CT being better

-- major procedure related complications:

    -- CT: 9 patients (0.5%)

        -- nonfatal MI in 3 (0.2%); complications leading to prolonged hospitalization >24h: 4/1793 (0.2%) for arrhythmia in 2, dissection of coronary or aorta in 2 (0.1%)

            -- only 1 complication in those only getting CT; 6 in those getting ICA after CT

    -- ICA: 33 patients (1.9%)

          -- nonfatal MI in 10 (0.6%); complications leading to prolonged hospitalization >24h: 11/1728 (0.6%), mostly for puncture site hematoma and skin/nerve injury; dissection of coronary or aorta in 2 (0.1%); cardiac arrest 2/1728 (0.1%)

    -- 4 of the complications were related to getting coronary artery bypass grafting (the rate of ICA complications was 4x as high in those undergoing revascularization)

    -- overall 74% decrease in complications in the CT group, HR 0.26 (0.13- 0.55)

 

-- angina, in the final four weeks of follow-up:

    -- CT: 8.8%

    -- ICA: 7.5%

        -- OR 1.17 (0.92- 1.48), not statistically significant

 

-- the rate of revascularization procedures was 24% lower in the CT group vs ICA: 256 (14.2%) vs 315 (18.0%): HR 0.76 (0.65-0.90)

-- quality of life:  EQ-5D visual analog scale and SF-12v2 physical component summary: no difference at 1.0 years

 

Commentary:

-- ICA is the reference standard for diagnosis of obstructive CAD and has the advantage of allowing revascularization at the time of the procedure; CT, however, is an accurate and noninvasive alternative, as has been found in several prior studies

-- Elective ICA has been reported to reveal obstructive CAD in only 38-50% of patients who were referred for the procedure in the US and Europe (and, several studies have suggested that about 30% of ICAs are not clinically indicated); though, as noted above, the vast majority of those with CAD on CT angiography as an initial test had significant CAD on the ICA

 

-- This study supports the conclusion that CT, with its low risk of adverse events, accurately identifies patients who are candidates for coronary vascularization in terms of subsequent actual clinical cardiovascular events, and CT might be considered an initial strategy as opposed to functional testing first (e.g. exercise EKG, and nuclear stress testing, stress echocardiography) in those with stable symptoms.

-- the SCOT-HEART trial found that when CT was added to standard care (including functional testing) versus standard care alone, that CT was associated with 41% lower risk of  death from CAD or nonfatal MI at 4.8 years vs just the standard care; the PROMISE trial, comparing an initial strategy of functional testing with exercise electrocardiography, nuclear stress testing or stress echo found that an initial CT in those with stable symptoms had similar cardiovascular outcomes at 25 months

-- and, two small studies found that initial CT strategy was associated with a lower number of invasive procedures, a higher (75%) risk of subsequent coronary angiogram showing obstructive CAD (ie was a good predictor of ICA finding obstructive CAD), and had similar clinical outcomes (hospitalizations and revascularization)

 

-- it is important to emphasize, however, that both the ISCHEMIA trial (http://gmodestmedblogs.blogspot.com/2020/05/ischemia-trial-stable-angina-conserv.html ) and the earlier COURAGE trial found that the optimal management of stable angina is aggressive conservative management and not interventions such as ICA. And, looking at the medication data in the above DISCHARGE trial (which was, by the way, buried deep in the supplementary material), medical management was clearly very suboptimal, with <50% on b-blockers or nitrates (and all had angina, albeit stable), and only 1/2 on statins...... And there was no comment on patients' blood pressure or lipid levels in the paper or supplement (so, how optimal was the medical management really????).

    -- the background here is that CAD is typically a diffuse disease, many of the "culprit lesions" (those found on early angiography that led to a subsequent acute coronary syndrome) are not those with lots of stenosis but in fact smaller, newer atherosclerotic lesions with large lipid cores (and attendant inflammation): older data found that 78-97% of the culprit lesions in people having an acute coronary syndrome were in arteries with <75% stenosis and half in those with <50% stenosis, which is typically considered not so significant).

        -- the main clinical goal of ICA in those with stable angina is relief of anginal symptoms. which all means: it is really unclear how many of these patients actually needed ICA at all, since they had stable angina and did not seem to have had optimal treatment initially with aggressive medical management.

        -- and doing the CT angiography seemed to stratify well this group with intermediate pretest probability of obstructive coronary artery disease into those who actually had it or not (the former being the ones requiring the aggressive medical management)

 

-- there were fewer revascularization procedures in those getting just CT, which is particularly significant in the setting that clinical MACE outcomes trended to be much lower in those getting only CT. (And, of course, it is clinical outcomes that matter.) it would be interesting to know why. is it happenstance? is it because more scary lesions are found by ICA than CT, though some of these scary ones do not pan out as being significant? Or perhaps these scary lesions were clinically treated and were amenable to medical management (statins can actually change the lipid composition of a plaque within 6 weeks or so), and we have no granular data as to who was treated aggressively and what their lipids/blood pressure/etc was? is it just that the number of such lesions is too small to evaluate rigorously in a study this size? is it because the patient is already having an invasive procedure (ICA), so might as well put in a stent while one is there? is it because there were too aggressive approaches despite lack of clearcut evidence of benefit???

-- no significant difference in angina symptoms between the groups, which is the main reason for invasive cardiac procedures in this group; though, again, seems like really suboptimal medical management beforehand. And still no benefit with the invasive procedure

-- another issue with invasive cardiac studies: there certainly is radiation exposure with CT, though also with nuclear medicine and ICA:

    -- a study done several years ago suggested that coronary artery calcium scores (see below) has about 1.5 mSv of radiation (background annual radiation is about 3 mSv), CT angiography has 1-4 mSv, nuclear stress test 3-4 mSv), per https://www.ahajournals.org/doi/10.1161/circulationaha.110.017665 , though studies have published a broader range than this. ICA is more like 7 mSv and if associated with a percutaneous coronary intervention (eg stent) more like 15 mSv

    -- and, of course, the risk of cancer increases with increasing dose (see http://gmodestmedblogs.blogspot.com/2018/06/low-dose-radiation-and-subsequent.html and for all of the prior blogs on this http://gmodestmedblogs.blogspot.com/search?q=radiation+cancer&updated-max=2015-02-16T13:10:00-08:00&max-results=20&start=4&by-date=false ). A 2012 Lancet study in the UK of people <22yo found increasing risk of brain cancer and leukemia in those getting a cumulative dose of more than 5 mSv (see https://pubmed.ncbi.nlm.nih.gov/22681860/ )

-- the functional testing can be quite unpleasant: using adenosine, dobutamine, dipyridamole, regadenoson, .... can be quite uncomfortable

-- this study assessed the probability of having CAD based on a pretest likelihood that was intermediate: this intermediate group is in fact precisely the one where further assessment is the most appropriate, since formal testing in  this intermediate pretest assessment have the highest potential of stratifying patients into higher or lower risk groups. And this study found that initial CT angiography was as good (maybe better) than invasive evaluation in predicting future clinical outcomes

 

--a related issue is the results of coronary artery calcium scoring, CAC, which is perhaps the best noninvasive marker of subsequent CAD events (CAC can be accessible when doing CT angiography, though no comment in this study).  of note, the JUPITER trail (see https://www.nejm.org/doi/pdf/10.1056/nejmoa0807646 ) found that hs-CRP levels (a marker of inflammation) predicted cardiac events, but on deeper analysis the hs-CRP added nothing to the risk model if coronary artery calcium scores were included. The MESA Jupiter trial added strong data to support CAC determination (see https://www.acc.org/latest-in-cardiology/articles/2014/07/18/16/29/the-mesa-jupiter-trial ): overall those with no coronary artery calcium (Agaston score of 0) have remarkably low CAD risk and found no difference in 12-yr risk whether on a statin or not, those with Agaston scores 1-100 do have possible benefit (not statistically significant but this group has pretty large risk of increasing CAC scores over time), and those with Agaston >100 have great statin benefit: see https://pubmed.ncbi.nlm.nih.gov/30409567/ ). It should be noted in this study that the mean age was 50, and since the current life expectancy in the US is 30 years later (currently almost 80), a 12-year life expectancy as in this study in people at low-to-medium risk may not be particularly meaningful in a progressive disease such as CAD. the 12-year window only brings the average up to the not-so-ripe-old-age of 62, so perhaps a 20+ year horizon would be more revealing...

 

Limitations:

-- this was not really a double-blind trial, since patients and clinicians were aware of which group the patient belonged to. this does introduce a bias into assessing the results

-- there may have been more silent events (eg MI) detected in the ICA group since they were monitored more aggressively during and after the procedure, affecting the comparative results of complications

-- as above, this study did not select patients with functionally limiting angina despite optimal medical therapy both to decrease further atherosclerosis or to treat the angina. The cohort overall seemed to be far short of “optimal” treatment

-- also, this trial was not designed to look specifically at a large group of people at intermediate risk of obstructive CAD and evaluating primary CT angiography vs doing primary functional testing (stress testing), with possible CT vs invasive procedure if positive. so, it is not clear from this study that primary evaluation with CT is the best approach (though other studies noted above do support this approach)

 

so, this study does add to prior ones suggesting that those people at intermediate CAD risk might do very well with just getting the CT angiography. Not a huge radiation dose, and seems to bypass some of the other tests, which may have significant radiation exposure (esp nuclear medicine) or use meds that are not particularly easy on one's body (adenosine, dipyridamole, regadenoson, dobutamine....). One major problem with this paper is that if one accepts that stable angina is primarily a medical and not surgical condition (which studies do suggest), then the first goal is optimization of medical management, followed by ICA only if medical management is insufficient. And, interestingly, they found that the usual reason for referral of patients for invasive assessment who are on optimal medical management (stable angina) found no advantage to ICA over CT, nor any difference in the quality-of-life indicators measured.  All of this is in the setting of about 30% of invasive cardiac procedures being NOT clinically indicated......  so, sounds like the way to go is CT angiography in those with intermediate pretest risk of obstructive CAD and stable angina. And those having CAD with stable angina should really get aggressive medical management, even with very low targeted LDL levels (eg see http://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html )

 

geoff

 

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