Friday, August 23, 2013
Only Large Changes in Spot Urine Albumin-Creatinine Ratio Likely Indicate Change in CKD Status
Only large changes in spot urine albumin-creatinine ratio (ACR) likely indicate a change in CKD status, according to a 157-patient American Journal of Kidney Diseases study. Day-to-day variability was substantial and increased in absolute terms, but decreased in relative terms, with increasing baseline ACR. For patients with normoalbuminuria, a change greater than 467% was required to indicate a significant change in albuminuria status with 95% certainty; for those with microalbuminuria, a change of 170% was required; for those with macroalbuminuria, a change of 83% was required; and for those with nephrotic-range proteinuria, a change of 48% was required.
Diastolic blood pressure below 70 mm Hg associated with higher mortality in chronic kidney disease
Achieving ideal systolic blood pressure (SBP) at the expense of lower-than-ideal diastolic blood pressure (DBP) could be harmful in adults with chronic kidney disease (CKD), noted a study.
A review of U.S. veterans with CKD found that SBP of 130 to 159 mm Hg and DBP of 70 to 89 mm Hg were associated with the lowest mortality rates.
Researchers looked at a retrospective cohort of 651,749 U.S. veterans with non-dialysis-dependent CKD and more than 18.5 million blood pressure measurements at all U.S. Department of Veterans Affairs health care facilities between 2005 and 2012.
All possible combinations of SBP and DBP were examined in 96 categories from lowest (<80/<40 mm Hg) to highest (>210/>120 mm Hg), in 10-mm Hg increments.
Results appeared in the Aug. 20 Annals of Internal Medicine.
Patients with SBP of 130 to 159 mm Hg combined with DBP of 70 to 89 mm Hg had the lowest adjusted mortality rates, and those in whom both SBP and DBP were concomitantly very high or very low had the highest mortality rates, researchers wrote. Patients with moderately elevated SBP combined with DBP no less than 70 mm Hg had consistently lower mortality rates than did patients with ideal SBP combined with DBP less than 70 mm Hg. Results were consistent in subgroups of patients with normal and elevated urinary microalbumin-creatinine ratios.
The researchers noted that paradigms emphasize treating the higher of the SBP or DBP readings, which ignores the potential negative effects of low pressures that are linked with their normal or elevated counterparts. In addition, they said, it is common in CKD for patients to have elevated SBP combined with low DBP.
They wrote, "Nearly one third (32.5%) of the patients in our cohort had SBP greater than 140 mm Hg and DBP less than 70 mm Hg at some point during the observation period. Our granular analyses of BP categories indicated that categories of lower SBP–DBP combinations are associated with lower mortality rates only as long as the DBP component remains greater than approximately 70 mm Hg."
An editorial noted that the observational data do not address causality and that "remarkable attenuation" in the adjusted analyses raises the specter of residual confounding.
The editorial stated, "It may not be the BP combination per se but the characteristics of the persons with that combination that lead to greater mortality rates. Also, the assumption outlined previously and implied by [the study authors] (that DBP and SBP move in tandem with treatment) may not necessarily be the case. Translating these findings into practice is challenging."
Low BP May Be Fatal in CKD
http://www.medpagetoday.com/Nephrology/
/41075
Low BP May Be Fatal in CKD
Published: Aug 20, 2013 | Updated: Aug 20, 2013
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Patients with chronic kidney disease (CKD), including those with diabetes, who were not on dialysis were more likely to die when blood pressure was too low, even if only on the diastolic measure, a veterans cohort showed.
Action Points
- This large VA-based study demonstrated that blood pressure, either too high or too low, was associated with increased risk of all-cause mortality in patients with CKD.
- Be aware that, due to the observational nature of the study, causality can not be determined. Patients with low blood pressure may have other comorbidities that predispose to adverse outcomes.
The relationship between systolic blood pressure and mortality followed a U-shaped curve that bottomed out at 130 to 159 mm Hg, while the J-shaped curve for diastolic pressure hit its optimal point at 70 to 89 mm Hg, Csaba P. Kovesdy, MD, of the VA Medical Center in Memphis, Tenn., and colleagues found.
Considered together, coming in a little high on systolic blood pressure appeared to be less risky than going too low with diastolic pressure, the researchers reported in the Aug. 20 issue of the Annals of Internal Medicine.
The likelihood of death for patients with an optimal systolic pressure of 130 to 139 mm Hg rose the lower the diastolic pressure went below 70 mm Hg. Adjusted hazard ratios were (all P<0.05):
- 1.09 at 60 to 69 mm Hg
- 1.14 for 50 to 59 mm Hg
- 1.37 for 40 to 49 mm Hg
- 1.91 for anything below 40 mm Hg
By contrast, for patients in the optimal diastolic range of 70 to 89 mm Hg, mortality risk changed relatively little as systolic pressure rose. Hazard ratios were 1.04 to 1.19 as blood pressure went up to 180 to 189 mm Hg and not significant beyond that.
"It may not be advantageous to achieve ideal systolic blood pressure at the expense of lower-than-ideal diastolic blood pressure in adults with chronic kidney disease," the researchers argued, adding "we suggest caution in lowering blood pressure to less than what has been demonstrated as beneficial in randomized, controlled trials."
The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend a treatment target of less than 140/90 mm Hg in CKD without proteinuria or less than 130/80 mm Hg if there is micro- or macroalbuminuria.
"These targets emphasize the lowering of systolic pressure, without considering the potential clinical effects of low diastolic blood pressure," Kovesdy's group noted. "Guidelines for lowering systolic blood pressure in patients with albuminuria will probably result in even lower diastolic blood pressure with treatment."
However, guidelines from the American College of Cardiology and American Heart Association for treating older adultssuggest caution in trying to reach the systolic goal of less than 140 mm Hg if diastolic pressure goes down to a "potentially dangerous level less than 65 mm Hg."
The study in CKD patients "reinforces an important note of caution for practicing physicians that in order to provide more protection to more patients, we must not concomitantly and unintentionally induce harm to a very large population of individuals at risk," Leopoldo Raij, MD, of the University of Miami and chief of nephrology hypertension at the Miami VA Medical Center, commented in an email toMedPage Today. Raij was not involved in the study.
The study took advantage of the large database of the VA healthcare system for a closer look at every combination of systolic and diastolic blood pressure -- 96 different categories in all -- in 10 mm Hg increments in relation to all-cause mortality over a median 5.8 years of follow-up.
Among the 651,749 veterans (mostly male; only 2.7% female) with CKD not dependent on dialysis, 43% had diabetes.
The highest mortality risk was at those extremes of blood pressure: about six-fold for less than 80/40 mm Hg and two-fold for more than 210/120 mm Hg.
Subgroup analyses didn't suggest different results for normal versus elevated urinary microalbumin-creatinine ratios.
The researchers suggested compromised blood flow to vital organs as a reason for the risk associated with too-low blood pressure, "especially low diastolic blood pressure compromising coronary perfusion," but acknowledged that confounding by stiff arteries or the high burden of comorbidities could have played a role.
Because the observational results couldn't determine causality, prospective randomized trial evidence is needed to clarify the best treatment goals in CKD and to see if active treatment improves survival in people with low diastolic pressure, they added.
"Specifically, we cannot conclude that the mortality risk associated with various blood pressures in our study is equal to the risk imparted by the same blood pressures when they occur as a result of antihypertensive interventions in clinical practice," the group cautioned.
Other limitations were the almost-exclusively male population, the potential for residual confounding, the relatively low proportion of patients with measurements of albuminuria, and use of clinic-measured rather than ambulatoryor research-quality measurements of blood pressure.
The study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the U.S. Department of Veterans Affairs (VA).
Kovesdy reported grant funds from the NIDDK and non-financial support from VA.
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Add Your Knowledge ™
Primary source: Annals of Internal Medicine
Blood Pressure and Mortality in U.S. Veterans With Chronic Kidney Disease: A Cohort Study
Ann Intern Med. 20 August 2013,159(4):233-242doi:10.7326/0003-4819-159-4-201308200-00004
http://annals.org/mobile/article.aspx?articleid=1726794
EXTRACT
Background: The ideal blood pressure (BP) to decrease mortality rates in patients with non–dialysis-dependent chronic kidney disease (CKD) is unclear.
Objective: To assess the association of BP (defined as the combination of systolic BP [SBP] and diastolic BP [DBP] at the individual level) with death in patients with CKD.
Design: Historical cohort between 2005 and 2012.
Setting: All U.S. Department of Veterans Affairs health care facilities.
Patients: 651 749 U.S. veterans with CKD.
Measurements: All possible combinations of SBP and DBP were examined in 96 categories from lowest (<80/<40 mm Hg) to highest (>210/>120 mm Hg), in 10–mm Hg increments. Associations with all-cause mortality were examined in time-dependent Cox models with adjustment for relevant confounders.
Results: Patients with SBP of 130 to 159 mm Hg combined with DBP of 70 to 89 mm Hg had the lowest adjusted mortality rates, and those in whom both SBP and DBP were concomitantly very high or very low had the highest mortality rates. Patients with moderately elevated SBP combined with DBP no less than 70 mm Hg had consistently lower mortality rates than did patients with ideal SBP combined with DBP less than 70 mm Hg. Results were consistent in subgroups of patients with normal and elevated urinary microalbumin–creatinine ratios.
Limitation: Mostly male patients, inability to establish causality, and large number of patients missing proteinuria measurement.
Conclusion: The optimal BP in patients with CKD seems to be 130 to 159/70 to 89 mm Hg. It may not be advantageous to achieve ideal SBP at the expense of lower-than-ideal DBP in adults with CKD.
Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and U.S. Department of Veterans Affairs.
Fluoroquinolone Antibiotics May Increase Diabetics’ Risk of Dysglycemia
A study of more than 78,000 diabetic patients found that those taking fluoroquinolones had a higher risk of dysglycemia within 30 days of initiating the drugs than those taking other antibiotics. The incidence of hyperglycemia per 1000 persons was 6.9 for moxifloxacin and 1.6 for macrolides. The risk of hypoglycemia was 10.0 for moxifloxacin and 3.7 for macrolides. Patients taking levofloxacin, ciprofloxacin, and moxifloxacin were 1.75 to 2.48 times more likely to develop hyperglycemia and 1.79 to 2.13 times more likely to develop hypoglycemia than those taking macrolides. The findings are published in Clinical Infectious Diseases.
Surgeons Implant Lab-Grown Blood Vessel into Dialysis Patient
Researchers have developed a bioengineered blood vessel and successfully implanted it into the arm of a dialysis patient, according to a Duke Medicine press release. The procedure was part of a 20-patient phase I trial designed to test the vessel’s safety. The new vein is an off-the-shelf product with no biological properties that might cause rejection. Investigators engineered it by cultivating donated human cells on a tubular scaffold to form a vessel. They then cleansed the vessel of the qualities that might trigger an immune response. In preclinical tests, the veins have performed better than other synthetic and animal-based implants.
2 HCV Drugs Work Well Without Interferon
Two investigational drugs for hepatitis C (HCV), both taken orally, combined effectively in difficult-to-treat patients without the use of pegylated interferon, researchers reported.
Action Points
- This randomized trial demonstrated that the combination of faldaprevir and deleobuvir (without interferon) was relatively efficacious in treating hepatitis C, regardless of dosing regimen or duration.
- Be aware that the one arm of the trial which omitted concurrent ribavirin therapy fared significantly worse.
The drugs -- faldaprevir and deleobuvir (plus ribavirin) -- led to undetectable HCV 12 weeks after the end of treatment in 52% to 69% of patients, without the need for interferon, according to Stefan Zeuzem, MD, of the Johann Wolfgang Goethe University Medical Center in Frankfurt, Germany, and colleagues.
But efficacy was lower when investigators omitted the standard HCV drug ribavirin from the mix, Zeuzem and colleagues reported in the Aug. 15 issue of theNew England Journal of Medicine.
The current standard of care for the hard-to-treat genotype 1 of HCV is interferon and ribavirin, in combination with one of the protease inhibitors telaprevir (Incivek)and boceprevir (Victrelis).
Faldaprevir is a protease inhibitor in the same class as telaprevir and boceprevir and has been found effective with interferon and ribavirin, with fewer side effects than the older drugs.
But researchers are trying hard to get rid of interferon, which is difficult to take and often leads to treatment discontinuation, so that it is unlikely faldaprevir will be used in that context.
Instead, investigators are testing it in combination with other so-called direct-acting agents that target the HCV itself, rather than boosting the immune system as interferon does.
The findings reported by Zeuzem and colleagues are "encouraging" and show that "more effective treatment with shorter duration and improved side effect profile" is on the horizon, commentedGyongyi Szabo, MD, PhD, of the University of Massachusetts Medical School in Worcester, Mass.
The study is the first large-scale trial to show "excellent therapeutic benefit of an interferon-free, all oral treatment regimen in genotype 1 chronic HCV infection," Szabo told MedPage Today by email.
They were randomly assigned to one of five study arms:
- 81 patients received faldaprevir at 120 mg/day plus 600 mg deleobuvir three times a day plus ribavirin for 16 weeks.
- 80 received the same regimen for 28 weeks, while another 77 received the regimen for 40 weeks.
- 78 patients got faldaprevir at 120 mg/day plus 600 mg deleobuvir twice a day plus ribavirin for 28 weeks.
- 46 patients got faldaprevir at 120 mg/day plus 600 mg deleobuvir three times a day, but without ribavirin for 28 weeks.
The primary endpoint of the study was the proportion of patients in each arm who had undetectable HCV 12 weeks after the end of therapy (SVR12).
But the study design also allowed Zeuzem and colleagues to determine if the dosage of deleobuvir, the duration of treatment, or the presence or absence of ribavirin had an impact on outcomes.
They also stratified patients by subgenotype 00 1a or 1b -- and by polymorphisms in the IL28B gene, which predicts response to treatment with interferon and ribavirin.
The investigators found that 59% of patients in the 16-week group met the primary endpoint, as did 59% of those who got the same dosing for 28 weeks and 52% who got it for 40 weeks.
Also, 69% of patients who underwent 28 weeks of therapy but with twice-daily deleobuvir had an SVR12.
On the other hand, just 39% of those who were treated without ribavirin reached an SVR12.
Deleobuvir dosing and treatment duration did not significantly affect treatment outcomes, Zeuzem and colleagues reported, but the response rate when ribavirin was left out of the mix was significantly lower (P=0.03).
SVR12 rates were higher among patients with genotype 1b infection, at 56% to 85%, compared with those who had genotype 1a disease, at 11% to 47%.
Also, patients with the IL28B CC polymorphism had SVR12 rates of 58% to 84%, compared with 33% to 64% among those with either CT or TT genotypes, Zeuzem and colleagues reported.
Adverse events were common, they reported, with 340 patients reporting at least one, 34 reporting a serious event, and 27 having an event that was life-threatening. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events.
Zeuzem and colleagues cautioned that the open-label design might have introduced a bias against the longer periods of therapy, since patients in those arms might have been more prone to early discontinuation.
They also cautioned that the lack of an interferon control group "limits the interpretation of the results in relation to the current standard-of-care treatment."
Szabo added that the response rate of at best 69% "is still far from a 100% desirable goal."
And, she told MedPage Today, patients in the study were Caucasian, which limits the applicability of the findings to other ethnic groups. African Americans with HCV, in particular, are known to be more difficult to treat.
In June, the U.S. Preventive Services Task Force recommended that all baby boomers be offered an HCV test, agreeing with the CDC, which in May 2012 urgedone-time screening for all people born between 1945 and 1965, a population believed to account for 75% of hepatitis C infections in the U.S. HCV is the most common chronic blood-borne pathogen in the U.S. and a leading cause of complications from chronic liver disease.
The study was sponsored, designed, and conducted by Boehringer Ingelheim in collaboration with the academic investigators. The sponsor monitored the study, collected data, and performed the statistical analysis. Zeuzem reported financial links with the company, as well as with Abbott, AstraZeneca, Achillion, Bristol-Myers Squibb, Gilead, Novartis, Merck, Idenix, Janssen, Roche, Vertex, Presidio, Santaris, and ITherX. Some co-authors are employed by Boehringer Ingelheim.
Primary source: New England Journal of Medicine
Source reference: Zeuzem S, et al "Faldaprevir and deleobuvir for HCV genotype 1 infection" N Engl J Med 2013; 369: 630-639.
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