creatinine increases after ACE/ARB may not be so good

A recent article in the BMJ challenged the long-held belief that ACE inhibitor/ARB related increases in creatinine were actually renoprotective (see RAS blockade inc creat cardiorenal risk bmj2017 in dropbox, or Schmidt M. BMJ 2017;356:j791).

Details:

-- observational study of 122,363 patients starting treatment with ACE inhibitor (ACE-I) or ARB from 1997 to 2014

-- they assessed the rates of end-stage renal disease, myocardial infarction, heart failure, and all-cause death among patients whose creatinine increased 30% or more after starting treatment, and also assessed the effect of each 10% increase in creatinine above the patient's baseline.

Results:

-- 2078 patients (1.7%) had a creatinine increase of 30% or more.

-- Comparing those with a creatinine increase of > 30%, vs those with < 30%:

    -- 56% female vs 46%

    -- median age 68 vs 63

    -- myocardial infarction in 10.5 vs 4.5%

    -- heart failure in 19 vs 4.8%

    -- arrhythmia in 17.2 vs 6.8%

    -- peripheral arterial disease in 6 ​vs 2.5%

    -- stage 3b CKD in 6.9 vs 3.7%/stage 4 in 2.0 vs 0.6%

    -- beta blockers in 23.7 vs 17%

    -- loop diuretics in 28.6 vs 7.2%

    -- potassium sparing diuretics in 8.8 vs 2.0%

    -- NSAIDs in 34.0 vs 23.5%

    -- underweight in 2.3 vs 0.9%, healthy weight in 26.9 vs 23.8%, overweight in 34.5 vs 38.4%, and obesity 29.0 vs  33.4%

    --so, basically those with greater creatinine increases had more baseline characteristics associated with increased morbidity/mortality

-- creatinine increases of 30% or more were associated with (adjusted for age, sex, calendar period, socioeconomic status, lifestyle factors, chronic kidney disease, diabetes, cardiovascular morbidities, and use of other antihypertensive drugs and NSAIDs):

    -- 3.43 times the rate of end-stage renal disease, incidence rate 3.43 (2.40-4.91)

    -- 1.46 times the rate of myocardial infarction, IR 1.46 (1.16-1.84)

    -- 1.37 times the rate of heart failure, IR 1.37 (1.14-1.65)

    -- 1.84 times the rate of all-cause death, IR 1.84 (1.65-2.05)

-- there was a greater increase for all outcomes as creatinine went from an increase of <10%, to 10-19%, to 20-29%, to 30-39%, and to > 40%

-- these results were consistent across calendar periods, subgroups of patients, and among those continuing to use ACE inhibitor/ARB's

-- there were much more dramatic increases in the rate of renal failure during the 1^st year after starting ACE-I/ARBs (12.2-fold increase) versus in the 2^nd year (3.7-fold) versus 2^nd to 5^th year (1.7- fold), but then increase to 2.5-fold from 5 to 10 years. However the numbers were 

small and the trend was nonsignificant. However, there were similar trends for heart failure and mortality which were significant. Heart failure was initially 1.9-fold increase in the 1^st year but then settled in at 1.5-fold increase.

Commentary:

 -- one major concern is that only about 10% of patients receive the recommended monitoring of serum creatinine soon after starting ACE-I/ARBs and only 20% of those with an increase of >30% discontinue the drugs as is recommended.

-- It has been widely held that larger increases of creatinine after taking these medications (up to 30%) were in fact renoprotective, supported theoretically/mechanistically that by decreasing intra-glomerular pressures, we were sparing the fragile glomeruli from barotrauma. These data were not terribly rigorous. For example, there was a small study (Apperloo AJ. Kidney Intl 1997; 51(3): 793), which did find that in 40 nondiabetic patients with impaired renal function prior to therapy, those with a greater GFR decline after ACE-I had more stable renal function, and this decline was completely reversible after stopping ACE-I therapy at 4 years.) And this study has been cited in subsequent reviews as clear evidence that the higher the creatinine increase (up to 30%) the better...

-- the benefits of the study are its huge size, its real-world outcomes data and the fact that it represented the general UK population in terms of age/sex/ethnicity, the fact that they only looked at patients who had at least one year of being continuously in the registry before they were started on an ACE-I/ARB, and that they had long-term follow-up until the 1^st diagnosis of end-stage renal disease, myocardial infarction, heart failure, and all cause mortality.

-- However, the negatives of the study are that the patients who had more significant creatinine increases were clearly sicker and had more inherent likelihood of getting these clinical endpoints. Specifically, these patients were older, had more underlying chronic kidney and heart disease, and had more drugs that were potentially nephrotoxic. In particular the use of potassium sparing diuretics suggests the possibility that these patients had more severe hypertension or heart failure requiring these drugs (and the study did not stratify the degree of these conditions at baseline). The increased use of NSAIDs might signal that these patients had more pain, were less ambulatory, perhaps more overweight (though the BMI of those with more a bump in creatinine was actually lower, the specific individuals who went on to renal failure may well have been those with a higher BMI and on NSAIDs, but these data not available), and were less able to have a healthy lifestyle, which has repeatedly been associated with increased morbidity/mortality. And, though they did mathematically model to compensate for the array of potential adverse biases, there was such a divergence in the baseline characteristics of the 2 groups (>30% versus <30% creatinine increase) that I do not trust this mathematical manipulation to compensate for the real potential biases between the groups. (in addition, they did not comment on the underlying clinical conditions of the patients comparing those with  <10% increase in creatinine vs those with >30%, but only for those <30% vs >30%)

-- It was also notable that pretty much all of these outcomes were much more dramatic in the 1^st year after starting ACE-I/ARBs, suggesting that we should be doing increased surveillance particularly in that 1^st year.

-- There are some perhaps relevant prior studies which suggest that increased creatinine is associated with cardiovascular disease, found in patients with mild to moderate renal dysfunction. However, these were patients with intrinsic renal disease as opposed to medication-induced increases of creatinine. So, not sure this is directly applicable to ACE-I/ARB-induced creatinine increases, but the above results are consistent with this.

-- We also did not know the levels of proteinuria of these patients, so there could be an important unaccounted for bias here. The studies suggesting the renoprotective effect of ACE-I/ARBs in diabetics found renal protection in those with proteinuria, even at low levels of albuminuria.

There have been other studies showing that patients with very significant proteinuria, especially those with greater than 1 g of albumin per day, do have renal protection by ACE inhibitors (see GISEN group. Lancet 1997; 349: 1857, which found that in 352 nondiabetic patients with proteinuria of 3 g of more than 24 hours, ramipril led to significant decreases in proteinuria as well as the rate of GFR decline, and a subsequent study of 186 patients with 1 to 3 g of proteinuria also had renal protection, but to a lesser degree, see Ruggenenti P. Lancet 1999; 354: 359.)

so, this article does give some pause. Perhaps our model of renoprotection is not so accurate. It is notable that the new JNC 8 guidelines do not recommend using ACE-I/ARBs as the primary treatment for hypertension in diabetic patients. Also the new American Diabetes Association guidelines (blog to come out soon) comment that those with diabetes should be treated with ACE-I, ARBs, thiazides, or dihydropyridine calcium channel blockers (no preference, except they recommend ACE-I/ARBs in those with albumin to creatinine ratio is greater than 300 mg/g, level A recommendation, or in those with 30 to 300 mg/g,  level B recommendation). 

So, what is the bottom line here? I am really not sure, pending other studies (and the best being an RCT). But this study does bring up the thinness of the prior assertions that those with ACE-I/ARB induced creatinine increases do better, and also reinforces the importance of checking creatinine (and lytes) after starting these meds, and stopping them if >30% increase. Otherwise, I am hesitant to change current practice.