ISCHEMIA trial stable angina: conserv management as good

As a small detour/reprieve from Covid:

 

Finally, the ISCHEMIA Trial was published (see cad stable med management ISCHEMIA Nejm2020 in dropbox, or  DOI: 10.1056/NEJMoa1915922). I have no idea why it took almost 6 months to publish this, given that almost all key papers presented at the American Heart Association are published simultaneously with their presentation in New England Journal. This delay also happened with the IMPROVE-IT trial with ezetimibe. does sound a bit fishy..

Details:

-- 5179 patients with moderate or severe ischemia were randomized to initial invasive strategy (angiography and revascularization when feasible) and medical therapy, vs medical therapy alone and angiography if medical therapy failed. Intensive medical therapy was applied to both groups equally

-- patients were recruited from 2012 to 2018 from 320 sites in 37 countries

-- median age 64, 77% male, 66% white/4% black/29% Asian/16% Hispanic

-- hypertension 73%, diabetes 42% (insulin use 10%), never smoked 43%/former smoker 45%/current smoker 12%, family history of premature CAD 26%, prior MI 19%, prior PCI 20%, prior CABG 4%, history of heart failure 4%/LVEF 60%

-- history of angina in 90%, increasing angina frequency in 26%, daily or weekly angina 20%, no angina in the past 4 weeks 35%

-- risk factors (all similar for conservative vs invasive groups): blood pressure 130/80 mmHg; total cholesterol initially 154 mg/dL, decreasing to 131 mg/dL in both groups by end of the study; HDL 43 mg/dL; LDL initially 83 mg/dL, decreasing to 64 mg/dL by end of study in both groups; triglycerides 124 mg/dL, decreasing to 112 mg/dL in both groups; A1c 6.3%; BMI 28; current smoking initially 12% decreasing to 10% by end of study

--medications: aspirin 97%, clopidogrel 26%, anticoagulants 7% (antiplatelet or anticoagulant: 100%), ACE inhibitor/ARB 69%, overall adherence to medications was initially 74%, increased to 81% on the last visit

-- patients with stable coronary disease had a clinically-indicated stress test showing moderate or severe reversible ischemia on imaging tests or severe ischemia on exercise testing without imaging

-- coronary computed tomography angiography (done in most patients) results:

    -- 1-vessel disease 24%, 2-vessel 31%, 3-vessel 45%

    -- left main disease in 1%, left anterior descending 87%, proximal LAD 47%, left circumflex 67%, right coronary 69%

-- exclusion criteria were: eGFR <30, a recent acute coronary syndrome (ACS), unprotected left main stenosis of at least 50%, LVEF <35%, NYHA class III or IV heart failure, and unacceptable angina despite the use of medical therapy at maximum acceptable doses

-- primary outcome: composite of death from cardiovascular causes, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest

-- secondary outcome: death from cardiovascular causes or MI

Results:

-- over a median 3.2 years: 318 primary outcomes events in the invasive strategy group vs 352 with the conservative strategy group

-- at 6 months: cumulative event rate was:

    -- invasive strategy group: 5.3%

    -- conservative strategy group: 3.4%

-- at 5 years (which is longer than the median time of the study, so may be subject to more statistical error):

    -- invasive group: 16.4%

    -- conservative group: 18.2%

-- similar results for the key secondary outcome

-- secondary analysis by MI definitions:

    -- periprocedural MI: 70 patients in invasive group (2.6% within 6 months) and 24 with medical management alone (0.3% within 6 months), with 5-yr cumulative rates was 3.8% vs 1.1% [these numbers were buried in the supplemental appendix and not expanded upon: i assume that the increase in the medical only group was from crossover to invasive strategy]

        -- in the conservative strategy group: 26% had angiography and 21% had revascularization (and almost always before the occurrence of the primary outcome event)

    -- cumulative incidence of stroke was more common in the invasive group at 6-month (5.8% vs 3.5%) and 1-yr (7.6% vs 5.7%)

    -- cumulative CV death, MI, or stroke risk was also higher in the 6-month (5.3% vs 3.0%) and 1-year (6.9% vs 4.9%) 

-- mortality:

    -- invasive group: 145

    -- conservative strategy: 144

--no evident difference in primary outcome with respect to baseline characteristics, including type of stress test, baseline LVEF, eGFR and age

--and, a subgroup analysis of those with less than moderate ischemia had no effect on the outcomes

Commentary:

--this trial, done in patients with moderate or severe stable angina, found that there was no difference with maximal medical management augmented by PCI or not. a few issues:

   -- the medical management of patients in the above study was pretty incompletely reported: all of the data on lipids, blood pressure, smoking, and diabetes were buried in the supplementary material, and there was no mention of use of other medications for chronic stable angina, such as beta blockers and long-acting nitrates. also no  comment on need for sublingual nitrates in each group. or changes in their exercise tolerance

    -- there was no mention of other important risk factors, such a diet, exercise, psychosocial variables

    -- there was a pretty significant crossover: 21% assigned to the medical therapy group did get a PCI done. no mention as to why.  acute coronary syndrome? uncomfortable amount of angina at baseline or getting worse enough for patients to want an invasive approach?  enticed by an intervention/Munchausen's???

--one comment they make is that periprocedural MIs are less severe than spontaneous MIs, which is generally true from several studies, but:

    -- the periprocedural MIs happen sooner, so any resulting morbidity or mortality happens at an earlier age with potentially longer period of disability (including psychological disability from having had an MI)

    -- there was no comment about what percent of the patients randomized to intensive management actually had PCI after their angiography was done (the trial was setup as the invasive group having angiography and revascularization when feasible. how often was it feasible and successfully performed?)

    -- the main granular study they quote on periprocedural MIs was the  ACUITY trial (see cad revasc ACUITY JACC2009 in dropbox, or doi:10.1016/j.jacc.2009.03.063), which was a study of those with acute coronary syndrome, and in fact had: mortality at 30 days: 5% with spontaneous MI, 3.2% with periprocedural MI, and 0.8% without an MI; at one year 16% vs 6% vs 2.6%.  so, PCI was not exactly benign (as was found in ISCHEMIA)

    -- overall, there seems to be a small serious complication rate with PCI: <0.5% need emergent CABG; a Cleveland Clinics study of death within 30 days of PCI: 47 deaths attributable to the procedure in 4,078 patients (eg 1%): see cad pci mortality JACC2013 in dropbox, or doi.org/10.1016/j.jacc.2013.03.071)

-- the ISCHEMIA study did involve a sicker population than in some prior studies, including patients with evidence of moderate or severe ischemia, suggesting benefit along the spectrum of stable angina

-- mechanistically the outcome of the ISCHEMIA trial does make sense: 

    --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, 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.

    --but for stable angina: this is more related to the degree of stenosis, where there is a mismatch of stress-related oxygen requirements by the heart vs the decreased blood flow providing the necessary oxygen.  PCIs open the stenotic vessels, improve flow and  decrease angina/improve quality of life. but studies have pretty consistently shown that PCIs offer no mortality benefit, as above with the ISCHEMIA trial and the prior COURAGE trial (for their 7.9 year folowup, see https://www.ahajournals.org/doi/10.1161/CIRCOUTCOMES.118.005079 )

    -- and, just mechanically performing the PCI has procedure-related morbidity/mortality, especially from periprocedural MIs and strokes

limitations of study:

--to me, mostly that there was not enough information about the specific noninvasive interventions done (given the importance of diet, exercise, psychosocial issues, stress) which are important risk factors for adverse cardiac outcomes. or even details of how often PCIs were done in the invasive group and how often they worked.

    --one might assume that the noninvasive medial interventions were equivalent in the 2 groups through the randomization of lots of people. But it would have been informative to know what the study researchers did or didn't do in terms of how clinicians can generalize their approach to individual patients (for example, reinforcing the low LDL target that they achieved at 64 mg/DL; but also suggesting that there might have been even more benefits if we reinforce diet/exercise/stress reduction in our maximal medical intervention strategy)

--and they did not provide info about the other meds used for the angina (eg b-blockers, nitrates) and how effective they were for anginal symptoms

--but a real plus is that this was a large multinational study, making generalizability easier (though it might have been useful to see the specific data for different countries, and if they had different nonmedical management strategies/what their outcomes were)

so, a few points:

-- perhaps the main point in the ISCHEMIA trial: patients with pretty severe ischemic disease and likely both large stenotic lesions (hence the stable angina), with many/most probably also having many small/newer/more lipid-rich lesions (and vulnerable atherosclerotic plaques), that simply maximiizing their medical therapy had profound effects both in direct cardiovascular outcomes (pretty low 5-year event rate) as well as in subsequent PCIs. and that in general PCIs do not prevent serious cardiovascular outcomes and even seem to increase their risk

-- the finding that intensive medical management is the best baseline strategy for patients with even severe ischemia but stable angina reinforces and extends what has become (i think) mostly standard practice.

    -- though even recent data suggest that about 30% of cardiac caths (which often lead to PCIs) are still not appropriate... 

-- and, it seems to me to be clinically important to achieve at least the target of the measured risk factors achieved above, as well as focusing on general healthy issues that also decrease cardiac events (eg Mediterranean diet, consistent exercise program, whatever we can do to help decrease stress, etc)

    --there might even be better outcomes with lower blood pressure goals (eg see: http://gmodestmedblogs.blogspot.com/2017/11/new-aha-hypertension-guidelines.html ) and lower cholesterol levels (see http://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html)

geoff

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