PARADIGM-HF trial

Do Neprilysin Inhibitors Have a Role in Patients With CKD?

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Neprilysin inhibitors offer a new target for therapeutics. Neprilysin is an enzyme that degrades endogenous natriuretic peptides.[1] These peptides are secreted during times of fluid overload natriuretic peptidesthe heart (specifically the atrium) is stretched. The peptides signal the kidneys to increase elimination of salt to help reduce the excess volume, but neprilysin curtails that response by degrading natriuretic peptides. Unfortunately, the body can overcome the effect of neprilysin inhibitors by increasing production of angiotensin II. Thus, a combination of inhibitors (ie, neprilysin inhibitor plus angiotensin II-receptor blocker) could potentiate the effect of these peptides and facilitate a greater amount/duration of natriuresis that can restore the patient to euvolemia.

Indeed, in the PARADIGM-HF trial, a combination of sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin II-receptor blocker) resulted in improved cardiovascular outcomes.[2] In a subgroup analysis, the combination pill seemed to retard the progression of kidney function decline and generated the hypothesis that dual therapy could preserve kidney function better than monotherapy with an angiotensin II-receptor blocker alone. These findings formed the basis for the UK HARP-III trial.[3]

 

In the UK HARP-III trial, 414 patients with kidney disease were randomly assigned to receive sacubitril/valsartan versus irbesartan alone.[3] The patients had relatively mild-moderate kidney disease (estimated glomerular filtration rate [eGFR] of 45-60 mL/min/1.73 m2 and a urine albumin:creatinine ratio [UACR] of 177 mg/g or greater, or an eGFR 20-44 mL/min/1.73 m2, irrespective of UACR) and were followed for 12 months. The primary outcome was the measured kidney function at the end of the study period.

Unfortunately, the positive results seen with cardiovascular outcomes in PARADIGM-HF were not seen observed in the UK HARP-III trial. The mean eGFR was 35.5 mL/min/1.73 m2 and fell to 29.8 and 29.9 ml/min/1.73 m2 in the dual-therapy and monotherapy arms, respectively (P = .86). In the prespecified subgroup analyses, there were no differences in the eGFR at study’s end in either group when filtered for age, sex, magnitude of proteinuria, or etiology of chronic kidney disease. In fact, at no time point during the 12-month study period was the eGFR higher in the neprilysin arm than in the ARB arm.

What Are Your Thoughts on Neprilysin Inhibitors for CKD?

Despite the current negative findings, I wonder whether neprilysin inhibition can still have a role in patients with proteinuric kidney disease. While the majority of patients enrolled were assumed to have diabetic kidney disease, the mean proteinuria was 310 mg/g.

I also wonder whether a longer duration of treatment is required to see a difference in eGFR. I don’t think we should shut the door on neprilysin inhibitors just yet as they relate to renal protection.

What do you think? Is the UK HARP-III trial a definitive trial on this subject? What type of patients would you like to see enrolled in a future trial that studies neprilysin inhibitors? Tell us in the comments section below.

Lab-Confirmed Flu Virus Linked to Imminent Risk for Acute MI

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Patients with laboratory-confirmed influenza were about six times as likely to be admitted for acute MI in the following 7 days compared with the period comprising the prior and subsequent years, results of a cohort study show.[1]

The risk was especially pronounced in older patients and was independent of flu vaccination status or history of MI hospitalization. There was also a signal that other forms of respiratory infection can similarly raise the risk for MI admission.

The findings are consistent with a lot of prior research, acknowledged Dr Jeffrey C Kwong (University of Toronto, ON), but much of it associated MI with acute respiratory infections by undetermined pathogens, or with other indirect indicators of flu.

“This is the first one where we used lab-confirmed influenza as the exposure, and we found this association that was quite strong between influenza and MI,” he told theheart.org | Medscape Cardiology.

Kwong is lead author on the study, which was based on Ontario health insurance records of people tested for respiratory viruses from May 2009 to May 2014 and was published January 24 in the New England Journal of Medicine.

The results are “no surprise,” agreed Dr Scott David Solomon (Brigham and Women’s Hospital, Boston, MA), who wasn’t involved in the study. But, he added, “What’s novel here, and improves on prior knowledge, is that it goes down to the individual-patient level, and says that when somebody actually has confirmed influenza, that they are more likely to have an MI.”

Kwong and his colleagues state that the increased MI risk regardless of vaccination status should not be seen as evidence that influenza vaccinations are ineffective; the study wasn’t designed to explore that issue. It does suggest, however, “that if vaccinated patients have influenza of sufficient severity to warrant testing, their risk of acute myocardial infarction is increased to a level that is similar to that among unvaccinated patients.”

The study seems to strengthen familiar public health messages about getting flu vaccinations and taking measures to prevent the spread of respiratory viruses, especially for patients with cardiovascular risk factors. Despite such messages, vaccination rates may be low even in such high-risk groups.

Solomon pointed to a recent analysis based on patients with heart failure in the PARADIGM-HF trial that saw only about a 53% rate of vaccination for influenza in North America.[2]

“And that was surprising because these were people who are clearly at risk, and would clearly benefit from vaccination,” he said.

Even when the effectiveness of the season’s flu vaccination has been questioned, such as the current flu season, “getting some protection is better than getting no protection,” Kwong said.

Secondary prevention patients with heart disease “don’t question taking aspirin, they don’t question taking β-blockers, they don’t question taking blood pressure medications or statins. But a lot of patients question the value of getting a flu shot,” he said.

“If you compare the effectiveness of influenza vaccination in preventing infection to statins in preventing MI, they shouldn’t be having second thoughts about getting a flu shot.”

Seven-Day Risk Interval

The analysis looked at 364 hospitalizations for acute MI in 332 patients that occurred within 1 year before and 1 year after laboratory confirmation of influenza; 48% in were women and 24% of the patients had been previously hospitalized for MI.

Of the 364 hospitalizations, 20 occurred during the first 7 days after the collection of a positive respiratory specimen, termed the “risk interval.” The remaining 344 hospitalizations occurred during the 2-year period made up of the year before and the year after the risk interval, termed the “control interval.”

The risk for MI hospitalization was increased sixfold during the risk interval compared with the control interval. Kwong said the group had expected the risk to fall off gradually, “but we actually saw that it just dropped down to nothing right after the first week. It’s really that first week where the risk is concentrated.”

Table 1. Incidence Ratios for Acute MI Hospitalization by Time After Laboratory Confirmation of Influenza

Interval Incidence Ratio (95% CI)
Days 1–7 6.05 (3.86–9.50)
Days 1–3 6.30 (3.25–12.22)
Days 4–7 5.78 (3.17–10.53)
Days 8–14 0.60 (0.15–2.41)
Days 15–28 0.75 (0.31–1.81)

 

The group also observed increased MI hospitalization risk associated with respiratory samples positive for viruses other than influenza. The implication may be that respiratory infections per se, not simply influenza, are associated with acute MI, according to Kwong.

“I think we just found that influenza risk seemed to be higher than that of the other respiratory viruses.”

Risk associated with influenza B was higher than with influenza A; Kwong said his group doesn’t have an explanation for the difference.

Table 2. Incidence Ratios for Acute MI Hospitalization by Specific Infections

Infection Incidence Ratio (95% CI)
Influenza A 5.17 (3.02–8.84)
Influenza B 10.11 (4.37–23.38)
RSV 3.51 (1.11–11.12)
Noninfluenza virus, non-RSV 2.77 (1.23–6.24)
Illness, no respiratory virus identifieda 3.30 (1.90–5.73)
RSV = respiratory syncytial virus. aFrom among influenza A, influenza B, RSV, parainfluenza virus, adenovirus, human metapneumovirus, coronavirus, or enterovirus.

 

Respiratory infections could trigger MI by any of several possible mechanisms, Kwong and Solomon observed.

Influenza elevates an array of proinflammatory cytokines that can lead to endothelial dysfunction, and possibly plaque rupture, but whether that’s the primary mechanism “is really just a postulate. We don’t know for sure that’s what is contributing,” Solomon said.

People with the flu also have increased oxygen demand, which might produce myocardial ischemia in someone with significant coronary lesions, he observed. Platelet activation is also increased.

“If the flu can trigger these events in people who are at risk, then it behooves us to do everything we can to minimize the risk associated with influenza,” Solomon said. “Obviously that means vaccination. And we are currently testing a strategy that might provide even better immunity in patients who are at risk.”

Solomon is a principal investigator for the ongoing Influenza Vaccine to Effectively Stop Cardiothoracic Events and Decompensated Heart Failure (INVESTED) trial, which has randomly assigned about 3000 of an estimated target of 9300 patients, he said.

INVESTED is comparing a high-dose trivalent influenza vaccine to a quadrivalent vaccine at a standard dose in patients with a recent history of hospitalization for MI or heart failure and other high-risk features. Mortality and cardiopulmonary hospitalization are the primary endpoints.