heart failure: less renal toxicity with angiotensin-neprilysin inhib; and cardiomyocyte regeneration

Many patients with heart failure also have renal insufficiency as either a comorbidity (perhaps related to a common underlying disease, such as diabetes) or as a result of heart failure treatment (loop diuretics, ACE/ARBs, etc). A  recent article suggests that the combination angiotensin-neprilysin inhibitor sacubitril/valsartan, a potent drug for heart failure with reduced ejection fraction (HFrEF), seems to have less renal toxicity and may therefore play an increasingly useful role in managing patients with HFrEF (See chf angio-nepril less renal toxicity jaccHF2018 in dropbox; or DOI: 10.1016/j.jchf.2018.02.004​)​.

Details:
--a secondary analysis of the PARADIGM-HF trial (see below), which compared sacubitril/valsartan vs the ACE-I enalapril in patients with HFrEF, assessed the renal toxicity of the regimens
--baseline: eGFR=70 (2745 patients, 33%, had CKD), median urinary albumin/creatinine ratio (UACR) was 1.0 mg/mmol (24% had increased UACR) 
--mean age 64, 22% female, mean EF 29%
--the achieved BP was lower on sacubitril/valsartan​ (6.7/4.0 mmHg) vs enalapril (3.6/2.5 mmHg)

Results:
--comparing eGFR in those on sacubitril/valsartan vs enalapril:
    ​--decrease of 1.61 ml/min/1.73m²/year (-1.77 to -1.44) vs decrease of 2.04 ml/min/1.73m²/year (-2.21 to -1.88), p<0.001
    --this decrease was similar in those with or without CKD at baseline
--creatinine safety thresholds:
    --3.3% on sacubitril/valsartan had creatinine >2.5 mg/dl during followup vs 4.5% on enalapril (p=0.007)
    --1.5% on sacubitril/valsartan had creatinine >3.0mg/dl during followup vs 2.0% on enalapril (p=0.10, though confidence interval was 0.55 to 1.06, making likelihood of benefit far outweighing likelihood of harm)

--comparing UACR in those on sacubitril/valsartan vs enalapril:

    ​--increase 1.20 mg/mmol (1.04-1.36) vs 0.90 mg/mmol (0.77 to 1.03), p<0.001

    ​--the increases were largely in patients going from normoalbuminuria to microalbinuria

--in patients having UACR increase>25%, sacubitril/valsartan was associated with slower rate of eGFR decline

--for patients developing ESRD or >50% decrease in eGFR: 37% lower with sacubitril/valsartan; HR 0.63 (0.42-0.95), p=0.028. no difference in those with or without pre-existing CKD

--there was no difference in relative risk reductions in cardiovascular death or heart failure hospitalization by eGFR, UACR or change in UACR (though primary outcome happened in 30% with CKD vs 21% without) [ie, those with CKD at baseline had a significantly higher likelihood of a primary outcome, but a higher absolute risk reduction of the primary endpoint with sacubitril/valsartan: more patients were likely to benefit]

--adverse events: study drug discontinued in 19.8% of those on enalapril vs 17.8% on sacubitril/valsartan, p=0.002

Commentary:
--the PARADIGM-HF trial was a drug-company supported trial that compared the use of sacubitril/valsartan vs enalapril in patients with HFrEF (see chf angio-nepril inhib nejm 2014 in dropbox, or DOI: 10.1056/NEJMoa1409077), finding that after 27 months there was a 20% decrease in death from cardiovascular causes or hospitalization for heart failure in those on sacubitril/valsartan vs enalapril 20mg/d, including a 20% decrease in cardiovascular deaths
--the concern, as noted above, is that these individuals with HFrEF are at higher risk of developing CKD by taking the usual heart failure meds, and that those with baseline CKD are at even higher risk of adverse outcomes. [however, though those with worsening renal failure have higher all-cause mortality, using ACE/ARB actually has more benefit in this subgroup than in those with stable renal function: see doi.org/10.1002/ejhf.13, similar to the above finding of absolute risk benefit with sacubitril/valsartan]
--interestingly, the improved renal outcomes with sacubitril/valsartan​ happened despite more lowering of blood pressure, where typically there is more worsening of eGFR using renin/angiotensin inhibitors
--unclear why sacubitril/valsartan had fewer adverse renal outcomes in the above study. perhaps this is related to improved cardiac function
--though the increase in UACR is somewhat concerning (and may be related to the effects of neprilysin inhibition), the increase was actually quite small and stabilized after a few weeks of treatment

so, this study, though a post-hoc analysis of an RCT, found that sacubitril/valsartan led not just to improved cardiovascular outcomes but also less renal toxicity, even in those with baseline renal dysfunction. this suggests an added indication for the med, not just to use this drug in patients who need more optimization of their heart failure therapy but also to consider using it in those with existing renal dysfunction or who have significantly worsening renal function on an ACE/ARB.

see http://gmodestmedblogs.blogspot.com/2017/05/new-heart-failure-guidelines.html  for the 2017 Am Heart Assn heart failure treatment guidelines, which includes their sacubitril/valsartan recommendations

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An interesting basic science study suggested that exercise, known to be beneficial clinically in people with heart failure, seems to stimulate the generation of new cardiomyocytes, both in normal hearts and in those post myocardial infarction (see chf exercise cardiomyocyte naturecommun2018 in dropbox, or DOI: 10.1038/s41467-018-04083-1). This was a study done in adult mice, since it is difficult in humans to document the generation of new  cardiomyocytes: cardiomyocytes are frequently polypoid and multinucleated, so it is often hard to distinguish the generation of a second nucleus or polypoidization from true mitosis. The technique used allowed the researchers to quantitatively discriminate between DNA repair and mitosis.

Details:
--8 weeks of voluntary exercise in mice (approx 5 km/day) led to a 4.6-fold increase in the birth of new cardiomyocytes (a projected rate of 7.5% vs 1.63% in sedentary mice)
--mice with an experimental MI (ligated LAD) had increased cardiomyocyte growth in the peri-infarct region independent of whether they exercised or not.  But, there was a much higher rate in the area distant to the peri-infarct, consistent with an exercise-mediated increase in cardiomyogenesis from 0.45 to 2.7% of total cardiomyocytes (p<0.001).
--exercise increases a specific microRNA (miR-222) in animal models and humans.  Giving the mice an miR-222 inhibitor completely blocked the new cardiomyocyte generation [microRNA is a small RNA which does not create protein (“non-coding”) but functions in modifying gene expression]

Commentary:
--the human heart has a low capacity to regenerate itself: about 1% of cardiomyocytes are renewed every year in young adults, and this rate decreases with age
--Fatal heart failure in animal models can be associated with surprisingly few cardiomyocytes lost, as few as 23 per 10,000 cells, an amount similar to apoptotic cardiomyocytes found in human heart failure. The extent of new cardiomyocytes generated by exercise is much higher than the apoptotic myocyte loss which can cause heart failure. Though, of course, these new cardiomyocytes will not develop in the same area that the old ones died (eg, in the scar tissue from an infarct)
--several trials have confirmed the clinical benefit of exercise in patients with heart failure both with reduced and with preserved ejection fractions (eg: see http://gmodestmedblogs.blogspot.com/2016/09/vigorous-exercise-helps-those-with.html  for a review of exercise in patients with reduced ejection fraction, or doi.org/10.1161/CIRCHEARTFAILURE.114.001615 for an article showing improved cardiorespiratory fitness and quality of life in patients with preserved EF who exercise, without changing either systolic or diastolic function). The benefit of exercise is comparable to many drug interventions. The postulate is that this increase in cardiomyocyte regeneration may be part of the mechanism whereby exercise improves cardiac function in both normal and diseased hearts.
--this also makes me wonder if one of the effects of lots of exercise is the increase in cardiomyocytes leading to the cardiac hypertrophy found in athletes (ie: "athlete's heart")

So, a study such as this one further reinforces and may help motivate patients with heart failure to be involved in regular exercise (which has the multitude of other benefits as well, as noted in many prior blogs: see http://gmodestmedblogs.blogspot.com/search/label/exercise )