ISCHEMIA subtrial for CKD patients: medical management wins again

A substudy of the ISCHEMIA trial assessed patients with stable coronary disease but advanced kidney disease, also finding no benefit from an invasive strategy over medical management  (see cad stable CKD med management ISCHEMIA nejm2020 in dropbox or DOI: 10.1056/NEJMoa1915925). See http://gmodestmedblogs.blogspot.com/2020/05/ischemia-trial-stable-angina-conserv.html for details/critique of the larger ISCHEMIA trial)

 

Details:

-- the ISCHEMIA-CKD study began enrollment 2 years after the ISCHEMIA trial, though the two ran in parallel and were conducted at most of the same sites

-- 777 patients with advanced kidney disease had moderate or severe ischemia on stress testing

-- all patients had an eGFR <30 (47%) or were on dialysis (53%)

    -- not on dialysis: median eGFR 23; dialysis: median duration 2 years/84% hemodialysis, 15% peritoneal

-- median age 63, 69% male, 64% white/8% Blacks/26% Asian, 61% moderate ischemia/38% severe, left ventricular ejection fraction 58%

    -- stress imaging in 82%/non-imaging exercise stress test in 19%

-- median anginal frequency: several times per month

-- cardiovascular risk factors: hypertension 92%, diabetes 57%, current smoker 11%, prior MI 17%, prior heart failure 17%, prior stroke 9%, PAD 6%

-- prior interventions: PCI 19%, CABG 4%

-- exclusions: patients who were very symptomatic, had heart failure or recent acute coronary syndromes, or an ejection fraction <35%

-- median LDL at baseline 83 mg/dL, and 70 mg/dL at the last visit; median systolic blood pressure was 135 mmHg baseline and 130 mmHg last visit

-- and, as opposed to the ISCHEMIA trial, coronary CT angiography was not recommended to exclude left main disease or non-obstructive CAD, given the risk of acute kidney injury from dye exposure

-- patients were randomized to a conservative strategy consisting of maximal medical therapy alone vs an invasive strategy of coronary angiography and revascularization, if appropriate, as well as maximal medical therapy.

    -- the invasive strategy group had coronary angiography within 30 days after randomization; the medical therapy group only had coronary angiography if they failed medical therapy (i.e. had an acute coronary syndrome, heart failure, resuscitated cardiac arrest, or angina refractory to medical therapy)

-- primary outcome: composite of death or nonfatal MI

-- a key secondary outcome: composite of death, nonfatal MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest

-- the researchers also tracked two sophisticated scores on angina related quality-of-life: the Seattle Angina Questionnaire, and the Canadian Cardiovascular Society angina class (however, results not reported yet)

-- median follow-up of 2.2 years

 

Results:

-- there was slightly more use of beta blockers in the medical management group (about 75% in each group), slightly more calcium channel blockers in the invasive group (about 55% in each). These differences were very small, but there was more use of “other anti-anginal medication” (not specified) in the medical management group, about 30% vs 20% in the invasive group

-- coronary angiography and revascularization:

    -- invasive group: 85% and 50% respectively (i.e. 35% of the patients who had angiography were not revascularization)

        -- 27% of patients had no obstructive coronary disease, the most common reason for not revascularizing

    -- multivessel coronary disease was present in 51% of patients, with involvement of the left anterior descending artery in 57%

 

-- primary outcome (composite of death or nonfatal MI):

    -- invasive strategy group: 123 patients

    -- conservative strategy group: 129 patients

    -- estimated 3-year event rate, for invasive vs conservative strategy: 36.4% vs 36.7%, adjusted HR 1.01 (0.79-1.29)

-- key secondary outcome:

    -- invasive vs conservative strategy: 38.5% vs 39.7%, aHR 1.01 (0.79-1 .29)

-- there was no significant difference in the individual outcomes: death from any cause, cardiovascular death, incidence of MI, hospitalization for unstable angina, or hospitalization for heart failure

-- there was a significantly higher incidence of stroke in the invasive strategy group, aHR 3.76 (1.52- 9.32), p=0.004; of note, this increased stroke incidence was more than 30 days after the procedure, not periprocedural strokes

-- incidence of death or initiation of dialysis in those not on dialysis at baseline was higher in the invasive group, largely driven by a higher incidence of newly-initiated dialysis

    -- the incidence of contrast-associated acute kidney injury in those undergoing coronary angiography or PCI was low compared to historic studies, at 8%

-- by MI type:

    -- overall MI rate: 67 patients in the invasive group, 60 in the conservative group; three-year cumulative incidence rates of 20.4% vs 16.9%, aHR 1.19 (0.84-1.69)

        -- procedural MI: 28 vs 11 cases, three-year cumulative incidence rates of 7.3% vs 3.1%, aHR 2.87 (1.42-5.79)

        -- non-procedural MI: 37 vs 52 cases, three-year cumulative incidence rates of 12.7% vs 14.2%, aHR 0.72 (0.47-1.09)

-- per pre-specified subgroups: only real difference was in the degree of baseline ischemia (though overlapping confidence intervals): invasive strategy seemed better in those with severe ischemia, adjusted HR 0.70 (0.46-1.05), but worse in those with moderate ischemia, a HR 1.30 (0.94-1.79)

 

Commentary:

-- this trial adds significantly to the literature, since most prior studies excluded patients with advanced renal disease

-- the issue of management of CAD in patients with severe CKD is extremely important, yet fraught with problems:

    -- both CAD and CKD are really common in the US population

    -- atherosclerotic disease is the major cause of death in patients with CKD, in part related to higher levels of traditional risk factors, but in part related to CKD itself as an independent risk factor

       -- there is an increased risk of all-cause mortality as well as cardiovascular mortality in those with even small increases in creatinine, as well as those with even low levels of microalbuminuria; and the combo is even worse

    -- there even are studies suggesting that CKD be considered a CAD risk equivalent, yielding about the same cardiovascular death risk as those with a history of myocardial infarction, or history of diabetes

    -- unfortunately, it can be harder to treat lipid disorders in those with CKD. The recent SHARP trial did find that those not requiring dialysis treated with a statin did have a significant reduction in cardiovascular events (though these patients also received ezetimibe). However LDL levels are often very high, and some of that may be related to high Lp(a) levels, which are not reduced significantly by statins or ezetimibe (ie, one should suspect that the issue is high Lp(a) levels when patients who are adherent to their statins still have very high LDL levels. Unfortunately high LP(a) is hard to treat: niacin helps, as does PCSK9 inhibitors).

        --lipoprotein(a), or Lp(a), is a structural combo of LDL plus apoprotein(a), wthe latter being a glycoprotein consisting of "kringles", one of which is similar to and competes with plasminogen; Lp(a) acts like both a proatherosclerotic LDL plus a prothrombotic moiety, is oxidizable (as is LDL), and is a documented bad actor in the atherosclerotic process

-- As with the larger ISCHEMIA trial, there are no specifics as to what was involved with intensive lifestyle interventions, either in the article or the supplementary appendix. This is an important omission: for example it is very clear that the composition of nutrients consumed, the level of exercise, occupational and environmental exposures (chemical, as well as stress-related), and psychosocial issues are important potentially modifiable cardiovascular risk factors that should be incorporated in a holistic approach to atherosclerotic disease prevention

-- it was interesting that the incidence of stroke in the invasive group was not periprocedural but later, suggesting subsequent atheroembolic complications (review of their graphs suggests that the curves were perhaps continuing to separate at 3 years); and that stroke was almost 4x the rate in those getting procedures.

    -- one additional comment here: there is a tendency in medical articles to list adverse events or have composite endpoints, comparing these compilations in the intervention vs control groups: this really is problematic (at least to me): there are fundamental differences between the individual items in the composites:

        --in the case of adverse events: having a stroke is a potentially really bad outcome, so a 4-fold risk is a really big thing and should not be in the same broad category as perhaps a somewhat shorter time to needing dialysis

        --in the case of composite primary or secondary outcomes: there is the combo of individual outcomes, largely because it is easier to reach statistical significance with a smaller number of participants by combining outcomes. but, again, there is a pretty big difference between dying and being admitted to the hospital for a nonfatal MI, or for heart failure (at least in this article they did look at the individual endpoints to see if there was a difference, though there still may not have been enough people in the study to find a statistically significant difference)

-- also, there was a high incidence of patients without obstructing coronary lesions in the invasive group. Unclear why. Perhaps a reduced accuracy of stress testing (ie false positives, though these patients were all symptomatic), or a greater prevalence of microvascular disease

    -- and, these patients all had significantly positive stress tests, so pretty likely there was significant arterial insufficiency (again, perhaps more in the microcirculation). though, it was pretty surprising to me that in these patients with really bad kidney disease along with lots of other bad cardiac risk factors, that 27% had no obstructing coronary atherosclerotic lesions and only 51% had multivessel disease....

-- as noted in the original blog on the ISCHEMIA trial (see http://gmodestmedblogs.blogspot.com/2020/05/ischemia-trial-stable-angina-conserv.html):  for acute coronary syndromes, older data found that 78-97% of the culprit lesions in people having an acute coronary syndrome are in arteries with <75% stenosis and half are in those with <50% stenosis. and the issue with ACS is that the newer, often smaller atherosclerotic plaques tend to have a larger lipid core (vs fibrosis), with its associated inflammation, thinner fibrous cap, and the combination of inflammation, associated cytokines, metalloproteinases, etc, leading to a much more vulnerable atherosclerotic plaque, more plaque rupture and then thrombosis creating a clinical acute coronary syndrome.  the good news is that dietary changes and statins can lead to plaque stabilization and decreased  vulnerability in just a couple of months (ie, maximizing medical management is the way to go to avoid ACS). so, not surprising that a targeted surgical intervention (eg PCI) does not matter so much.

   --though, there was a trend to be more benefit for revasularizing those with severe ischemia.  ??suggests that revascularization may help somewhat in those with severe disease by bypassing some of these vulnerable plaques.

 

So,

-- a useful study given the high prevalence of both chronic kidney disease and atherosclerotic disease, and the lack of clear guidance from prior studies

-- the study does confirm, as with the original ISCHEMIA trial, that stable angina is basically a medical disease that should be treated with maximal medical therapy. 

    --In fact, there are strong suggestions from newer articles that maximal therapy may include even lower LDL levels (http://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html ) and lower blood pressure levels (http://gmodestmedblogs.blogspot.com/2017/11/new-aha-hypertension-guidelines.html ) than in the study

-- but, one should also include the various nonpharmacologic (diet, exercise, etc) and psychosocial factors in optimizing therapy, focusing on an individualized, patient-specific holistic approach 

geoff

 

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