cardiovasc trials: patients with CKD usually not included

 As mentioned in many prior blogs on clinical trials, patients with chronic kidney disease (CKD) are often excluded from participating in the studies, which creates a real dilemma on whether the study results are applicable to the very large numbers of patients with CKD. A recent systematic review found that these patients have actually been excluded more often currently than 2 decades ago (see ckd underrepresentation in studies JAMA2024 in dropbox, or doi:10.1001/jamanetworkopen.2024.0427)

 

Details:

-- a systematic review of studies from ClinicalTrials.gov from 2000-2021, with further Internet searches if no fulltext publications were found, for studies that had at least 100 patients

-- these studies evaluated specifically the effectiveness of antiplatelets and anticoagulants, blood pressure lowering drugs, glucose lowering drugs, or cholesterol drug lowering drugs in adults with cardiovascular disease or cardiovascular risk factors

-- 1194 RCTs were found with 2,207,677 participants, with median follow-up of 24 months; 48% of the studies were multicontinental, 83% were drug-company sponsored 

-- mean age 63, 64% male, mean eGFR was 73 (by creatinine), and median (IQR) serum creatinine was 1.00 mg/dL; 17 studies (<1%) included patients on dialysis and 1 (<1%) had patients who had renal transplants

-- main outcome: evaluating the number of studies on meds for common clinical indications (antithrombotics, blood pressure lowering, cholesterol lowering, glucose lowering) that included patients with different levels of CKD

 

Results:

-- since 2000, the percent of cardiovascular RCTs that excluded patients with CKD increased from 66% to 79%, with 74% overall (884 RCTs) excluding these patients

-- patients with eGFR >30, serum creatinine <2mg/dL, or history of CKD (stages 1-3) were excluded from 458 RCTs; 38% of all RCTs and 52% of RCTs

-- overall, in the past 20 years, patients with CKD stage 4-5 have been excluded from RCTs more frequently; those with CKD stage 1-3 have had stable levels of exclusion

 

 

-- 864 RCTs (72%) found that more patients were excluded than anticipated on safety grounds (there was no explicit definition of what they meant by safety grounds, though they seem to feel that if no medication dose adjustment were needed, these were patients excluded but not for safety reasons)

    -- 306 (63%) of the trials required no dosage adjustment

    -- "561 of 706 RCTs (79%) excluded more patients with CKD than necessary on safety grounds"

        -- and over 80% of participants requiring dose adjustment because of their level of CKD were excluded 

 

 

-- 158 RCTs (13%) reported results for patients with CKD

-- 23 RCTs (2%) reported results for patients with an eGFR <30

-- 15 RCTs (1%) reported results for patients receiving dialysis

-- 1 RCT (0.1%) reported results for recipients of kidney transplant

 

-- per the medication types for the studies:

    -- blood pressure-lowering drugs: 221 studies, 19% of total

        -- major focus was on ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists (MRAs)

        -- all meds except a-blockers were evaluated patients with eGFR<60

        -- MRAs, ARBs, b-blockers, thiazides were assessed patients with eGFR<30

        -- ACE-I, calcium blockers were evaluated in those on dialysis

    -- cholesterol-lowering drugs: 162 studies, 14% of total

        -- mostly statins were tested in patients with CKD

        -- statins alone and with ezetimibe were evaluated in patients with eGFR<60

        -- PCSK9 inhibitors, niacin, and icosapent ethyl were also evaluated in those with eGFR<60

        -- for patients wtih eGFR <30, only combo of statin with ezetimibe were evaluated

        -- for those on dialysis, statins with and without ezetimibe were evaluated

    -- antiplatelets and anticoagulants: 221 studies, 19% of total

        -- these meds were the best group of meds checked for patients with CKD

        -- multiple RCTs assessed single- and double-antiplatelet therapy as well as DOACs in patients with CKD

           -- but, few studies assessed those with eGFR<45

        -- limited data on those getting dialysis (and only comparing DOAC to vitamin K antagonists)

        -- no information on those with kidney transplants

    -- glucose-lowering drugs: 552 studies, 46% of total

        -- very little info on older meds: metformin, sulfonylureas, insulin

        -- several RCTs were done in those on SGLT-2 inhibitors (13 studies), GLP-1 receptor agonists (10 studies), and DPP-4 inhibitors (6 studies)

        -- minimal information on those with eGFR <30

 

Commentary:

-- CKD is extremely common: 700 million people worldwide have CKD and CKD is a cause of 1.9 million cardiovascular deaths annually (cardiovascular deaths being the most common cause of death in those with CKD)

-- over 60% of patients CKD have a history of cardiovascular disease, a higher risk than for developing kidney failure, and this increased risk begins in those with eGFR<75, and increases with more severe renal failure, independent of the presence of diabetes and hypertension

-- as a result of this intimate link between CKD and cardiovascular disease, over 90% of these patients are prescribed medications to improve cardiovascular risk management (though, per above, very few studies actually included patients with CKD)

-- the overall conclusion from the authors of the current study was that “ significant evidence gaps in cardiovascular risk management interventions for all patients with CKD ... particularly for those with CKD stages 4 to 5” and, the reason for exclusion is inaccurately stated as being due to concerns about the safety and effectiveness of these interventions

-- of particular concern is that several new very important medications have come to the forefront in cardiovascular therapy (e.g. SGLT-2 inhibitors and GLP-1 receptor agonists), both of which have potential renal benefit, yet the actual studies in those with stage 4-5 CKD/dialysis/transplant are missing

-- and older patients are a large and increasingly population: excluding those with stage 1 or 2 CKD basically excludes almost everyone over age 60 (https://nccd.cdc.gov/ckd/AreYouAware.aspx?emailDate=September_2020#:~:text=Data%20from%20the%202015%E2%80%922016,aged%2020%20to%2039%20years.)

    -- using the eGFR calculator based on creatinine, a 70kg 60yo male with creatinine 1.0 mg/dL has stage 2 CKD per https://www.kidney.org/professionals/kdoqi/gfr_calculatorcoc 

-- though remarkably few studies included patients on dialysis or had a renal transplant, these folks are at very high cardiovascular risk and are quite plentiful: in 2018, 785,883 people in the US had kidney failure and needed dialysis or a kidney transplant to survive: 554,038 received dialysis and 229,887 lived with a kidney transplant (https://www.kidney.org/news/newsroom/fsindex#:~:text=In%202018%2C%20785%2C883%20Americans%20had,lived%20with%20a%20kidney%20transplant. ) 

-- this study found that not only was there no improvement in  including patients with CKD since 2000, but the number of cardiovascular RCTs with CKD patients actually decreased

    -- only 13% of cardiovascular RCTs included patients with CKD (and mostly in subgroup analyses, which do not have the same statistical rigor of assessing the effect of CKD as a primary outcome)

    -- and when CKD is considered, it is largely in patients with stage 3 and not more severe CKD (10% of studies of CKD patient included those with stage 4-5 CKD)

    -- overall, only 3% of cardiovascular RCTs  were designed explicitly to include patients with CKD

-- though commonly cited as "safety concerns" for not including patients with CKD in studies, there was no change over time in the proportion of studies done with medications requiring dose adjustments for CKD

-- one big issue in the above study is the accuracy of eGFR:

    -- these eGFRs are based on creatinine. there is a reasonable argument that eGFR based on cystatin or the combination of cystatin and creatinine are more accurate than one based on creatinine. And there was an important study (to me) that found that cystatin-based eGFR was much more predictive of future adverse cardiovascular and renal events: https://gmodestmedblogs.blogspot.com/2023/12/cystatin-c-better-predictor-of-bad.html

    -- and, though we base a lot of clinical decisions based on eGFR (medication dosing, when to stop using certain meds, etc), eGFR correlates poorly with the actual measured GFR: https://gmodestmedblogs.blogspot.com/2022/07/egfr-not-such-great-estimate-of-renal.html 

 

Limitations:

-- overall, the studies included in this systematic review involved patients with low levels of CKD: the median creatinine was 1.0, and only 11% had median creatinine of 1.5 or more

    -- as noted above, there are also quite likely big differences in patient outcomes in evaluating patients with earlier CKD (stage 1-3) vs more advanced CKD (stages 4-5), or those on dialysis or post-transplant. And, one cannot assume that a successful med trial in a patient with an eGFR of 55 (ie someone most likely to be included in a study) applies to these latter patients

    -- that all being said, it is important to remember that the trend in creatinine is important here: an increase from 0.5 to 1.0 mg/dL reflects a 50% decrease in renal function. so a creatinine of 1.0 mg/dL (which are typically considered "normal") could reflect a significant degree of CKD

-- 83% of the studies were drug-company funded, and drug companies are interested in designing these studies to get the best results for their drugs, with the best results likely to be in patients who are very healthy with few medical comorbidities (and CKD entails lots of potential comorbidities including a much higher risk of a cardiovascular event or finding further renal injury or other events related to their compromised health, including hospitalizations or death) that might confound their results. And this is despite the FDA and EMA (the European FDA) having focused on the importance of including patients with more advanced CKD in studies

-- as with systematic reviews overall, the researchers are combining many different studies with very different inclusion/exclusion criteria, different measurements, and different patient populations with very different psychosocial issues/diet/exercise (eg: diet and exercise, for example, seem to decrease the risk of CKD, per https://gmodestmedblogs.blogspot.com/2024/02/nonpharmacological-diabetes-remission.html , or https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10005115/ , 2 studies examples of studies finding that Mediterranean diet seems to prevent CKD and a modified Med diet can slow  CKD progression). A summation of these disparate studies into a systematic review can lead to inaccurate conclusions.

 

So, what does this all  mean?

-- one concern is what does "evidence-based medicine" really mean??? if rarified populations in one area of the world respond to a certain drug, but the results of the study do not apply to 90% of the world population, the moniker "evidence-based" seems to lose its luster. We clinicians are always making very specific individual patient decisions all the time, hoping that the information in the medical journals will apply to them. But does it? Are we exposing patients to untoward adverse reactions in the long term? those with CKD, largely excluded from important clinical studies, probably are predisposed to more renal injury or a cardiovascular event independent of the medication used in the trial, given their baseline not-so-great renal function.

-- we really do need to develop the best way to estimate renal function and institute a consistent policy for reporting it in studies and clinical work. And just using creatinine in some studies (likely the least good of the measures we use) but cystatin in others is one of those apples and oranges comparisons

-- as mentioned above, the major focus on eGFRs should be their trend and not a single calculation of eGFR based on one measurement of creatinine, for example.  It is very misleading to report out a creatinine of 1.0 mg/dL as being "normal", since this could be a very significant decrease in actual renal function

geoff

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