JACC

Relationship of Dapagliflozin With Serum Sodium: Findings From the DAPA-HF Trial

Posted by

0


Clinical Research

Abstract

Objectives

This study aimed to assess the prognostic importance of hyponatremia and the effects of dapagliflozin on serum sodium in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.

Background

Hyponatremia is common and prognostically important in hospitalized patients with heart failure with reduced ejection fraction, but its prevalence and importance in ambulatory patients are uncertain.

Methods

We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) and secondary outcomes according to sodium category (≤135 and >135 mmol/L). Additionally, we assessed: 1) whether baseline serum sodium modified the treatment effect of dapagliflozin; and 2) the effect of dapagliflozin on serum sodium.

Results

Of 4,740 participants with a baseline measurement, 398 (8.4%) had sodium ≤135 mmol/L. Participants with hyponatremia were more likely to have diabetes, be treated with diuretics, and have lower systolic blood pressure, left ventricular ejection fraction, and estimated glomerular filtration rate. Hyponatremia was associated with worse outcomes even after adjustment for predictive variables (adjusted HRs for the primary outcome 1.50 [95% CI: 1.23-1.84] and all-cause death 1.59 [95% CI: 1.26-2.01]). The benefits of dapagliflozin were similar in patients with and without hyponatremia (HR for primary endpoint: 0.83 [95% CI: 0.57-1.19] and 0.73 [95% CI: 0.63-0.84], respectively, P for interaction = 0.54; HR for all-cause death: 0.85 [95% CI: 0.56-1.29] and 0.83 [95% CI: 0.70-0.98], respectively, P for interaction = 0.96). Between baseline and day 14, more patients on dapagliflozin developed hyponatremia (11.3% vs 9.4%; P = 0.04); thereafter, this pattern reversed and at 12 months fewer patients on dapagliflozin had hyponatremia (4.6% vs 6.7%; P = 0.003).

Conclusions

Baseline serum sodium concentration was prognostically important, but did not modify the benefits of dapagliflozin on morbidity and mortality in heart failure with reduced ejection fraction. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]: NCT03036124)

Discussion

In a contemporary, well-treated ambulatory cohort of patients with HFrEF, most of whom had mild symptoms, the prevalence of hyponatremia was low (8.4%) and there were few cases of severe hyponatremia (0.06%). However, hyponatremia remained an independent predictor of outcomes despite adjustment for other prognostic variables, including NT-proBNP. The benefit of dapagliflozin was consistent across the range of sodium concentrations measured at baseline. Dapagliflozin had a small biphasic effect on serum sodium concentration. Initially, compared with placebo, dapagliflozin led to a small, although statistically significant, decrease in sodium. However, after 2 weeks, the opposite pattern was observed.

Although hyponatremia is recognized as the most common electrolyte disorder among hospitalized patients with HF, there are few reports of the prevalence of hyponatremia in ambulatory patients with HFrEF and none in patients comprehensively managed with contemporary guideline-recommended medical therapy.9-11 Even accounting for different definitions, the prevalence of hyponatremia in our outpatient cohort (8.4%) was less than half that reported in hospitalized patients (generally 20% to 25%).1-4

Although most cases of hyponatremia in the DAPA-HF trial were mild, low sodium still predicted worse outcomes. This excess risk persisted despite adjustment for other recognized prognostic variables, many of which showed an imbalance between patients with and without hyponatremia. Indeed, we know of no prior study where such extensive adjustment was made, including for natriuretic peptide level, in ambulatory patients. 9-11 Moreover, most studies to date have only reported the association between hyponatremia and all-cause mortality, whereas we have also shown that low sodium was independently predictive of worsening HF events (principally HF hospitalization) and symptoms.16,17

The prognostic importance of a single sodium measurement was remarkable given the rapid and frequent resolution of hyponatremia on rechecking blood chemistry. In the placebo group, almost half of cases of hyponatremia had resolved at the 2-week measurement after randomization and about two-thirds of cases had resolved by 8 months. This substantial recategorization occurred because the initial measurement was only slightly below normal in many patients. However, almost as many people in the placebo group developed new hyponatremia at each timepoint during follow-up as showed resolution of hyponatremia. Dapagliflozin had a surprising, previously unrecognized, biphasic effect on new hyponatremia. The incidence of hyponatremia was increased during the first 14 days after randomization but was decreased thereafter in patients treated with dapagliflozin compared to placebo. The explanation for this pattern is uncertain. The initial osmotic and natriuretic diuresis induced by SGLT2 inhibitors causes an increase in vasopressin secretion and a reduction in free-water clearance, experimentally and clinically, which might account for the early transient reduction in serum sodium concentration.18-21 The subsequent effects on serum sodium concentration are harder to predict given the direct effects of SGLT2 inhibitors and the compensatory responses to these. The diuresis induced by SGLT2 inhibitors is believed to lead to a reduction in intravascular volume and blood pressure, and the increased delivery of sodium to the distal nephron results in a decline in eGFR by inducing tubuloglomerular feedback.22-25 However, it has been hypothesized that SGLT2 inhibitors reduce blood volume less than conventional diuretics.26 Although the initial decrease in sodium mirrors the early decline in eGFR after starting dapagliflozin, subsequently, serum sodium concentration increased more in the dapagliflozin group than the placebo group, to the extent that the mean concentration was eventually significantly higher in the dapagliflozin group. Although the initial decrease in eGFR also partially recovers, eGFR does not recover back to the same level as in the placebo group (as is also observed in other trials and real-world data over the same period) and eGFR does not crossover as for sodium.27,28 So, it seems unlikely that the effect of SGLT2 inhibitors of eGFR alone explain the early effect on sodium, although it might explain the longer-term effect if there is a relative increase in free-water clearance with these agents (as seems likely) and sodium excretion is maintained (and sodium retention does not occur), which may be the case if eGFR is maintained. The complexity of these effects is reflected in the seeming paradox of the early decline in serum sodium concentration occurring contemporaneously with an increase in hematocrit, questioning whether the latter can be wholly explained by volume contraction. Although detailed analyses of change in hemoglobin have been reported in other trials, the effect of other SGLT2 inhibitors on serum sodium has not been reported.29 Irrespective of the possible mechanisms, the important overarching finding was that after 14 days, patients treated with dapagliflozin were less likely to develop new hyponatremia and more likely to show resolution of existing hyponatremia than individuals treated with placebo, which may be a favorable effect of SGLT2 inhibition in HF. The benefits of dapagliflozin on the primary and secondary cardiovascular outcomes were consistent in patients with and without hyponatremia (and across the range of serum sodium concentration at baseline), despite the initial transient small decline in serum sodium concentration. Indeed, the absolute risk reduction with dapagliflozin was 1.5- to 2.0-fold greater in patients with hyponatremia than in those without. Similarly, dapagliflozin was also well-tolerated in patients with hyponatremia, and the safety of dapagliflozin was similar in patients with and without hyponatremia.

Source: JACC

QT Prolongation After His Bundle Pacing: What Is the Mechanism?

Posted by

0


https://www.jacc.org/doi/10.1016/j.jaccas.2021.11.015?utm_medium=social&utm_source=facebook_post&utm_campaign=facebook_post

Absorb Stent Works Below the Knee

Posted by

0


‘Excellent’ results but only in unusually focal lesions.

Implanting the Absorb bioresorbable vascular scaffold in focal below-the-knee lesions was safe and effective in the long run, investigators suggested.

Technical success was achieved in all cases. And the majority of tibial and distal popliteal lesions treated with the everolimus-eluting disappearing scaffold improved at 1 year (79%), Ramon L. Varcoe, MBBS, MS, PhD, of Australia’s Prince of Wales Private Hospital, and colleagues reported online in JACC: Cardiovascular Interventions.

On Kaplan-Meier analysis, primary patency was observed in 96% and 84.6% of lesions at 12 and 24 months, respectively; freedom from clinically-driven target lesion revascularization was 96% at both time points. There was a 6% rate of binary restenosis over follow-up, the authors found.
They concluded that the numbers “demonstrated excellent safety, patency, and freedom from target lesion revascularization using the Absorb bioresorbable vascular scaffold below the knee.”
“It has significant potential to become the favored class of therapy in this group of patients,” they wrote.
“We congratulate the authors for reporting the long-term clinical outcome of their experience with coronary scaffolds in below-the-knee interventions; their restenosis rate, together with the appropriate duration of clinical follow-up, actually represent a proof of concept of the great potential of vascular scaffolds in peripheral interventions,” Antonio Micari, MD, PhD, and Roberto Nerla, MD, both of Maria Cecilia Hospital in Italy, wrote in an accompanying editorial.
Varcoe’s study included 33 patients with critical limb ischemia (68.4%) or severe claudication (31.6%). Operators treated 43 lesions with 50 Absorb scaffolds in total; five patients died over the follow-up period, leaving 38 treated limbs available for analysis.

Importantly, the investigators selected highly focal lesions for their study. The average lesion clot was just 19.2 mm long.
“This makes it impossible to derive reliable considerations about the usefulness and the real impact (in clinical practice) of these devices on below-the-knee procedures, given that infrapopliteal disease is known to be more diffuse and complex in a real-world setting,” according to Micari and Nerla, who suggested that future studies include a broader population.

Gender No Predictor of Prolonged DAPT Benefit

Posted by

0


Prolonged dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) effects don’t differ by gender, the PRODIGY investigators suggested.

On multivariable adjustment, recipients of extended and 6-month DAPT experienced similar rates of combined death, myocardial infarction, and cerebrovascular accidents at 2 years. This was true whether they were male (HR 1.08, 95% CI 0.766 to 1.522) or female (HR 1.013, 95% CI 0.588 to 1.748), reported Marco Valgimigli, MD, PhD, of Bern University Hospital in Switzerland, and colleagues.

 According to their study, published online in JACC: Cardiovascular Interventions, sex did not appear to play a role in the frequency of individual adverse outcomes. Notably, major bleeding occurred at similar rates across groups regardless of the definition used (included were the Bleeding Academic Research Consortium, Thrombolysis in Myocardial Infarction, and Global Use of Strategies to Open Occluded Coronary Arteries scales).

“Gender failed to emerge as a treatment modifier with respect to DAPT durationsuggesting that the decision-making on DAPT duration in female patients should weigh ischemic versus bleeding risks,” the authors concluded.

They noted that the longer duration won out in the landmark DAPT trial likely because of the selection of endpoints — stent thrombosis and the combination of MI and stroke.

While the secondary analysis of the PRODIGY trial, which randomized 1,970 patients to 6- or 24-month DAPT consisting of clopidogrel (Plavix) and aspirin, was only powered to find a 40% difference, it was in line with other trials that haven’t shown a significant impact on death or cardiovascular death, the researchers noted.

“When taken together, currently available studies suggest that the decision-making over DAPT duration towards either shorter or longer than conventional 12-month time frame should be a ‘patient by patient’ approach, aiming at balancing ischemic versus bleeding risks,” they concluded. “With that respect, whether gender per se should be taken into account in tailoring patient’s therapy is still unclear.”

 But what was clear from PRODIGY was that “gender should not be a primary covariate to be considered in the decision-making on DAPT duration after coronary stenting,” they added.

In the trial, women (n=459) were older and more likely to have hypertension, lower creatinine clearance, and acute coronary syndrome. Men, however, had a higher severity of coronary artery disease.

“The current findings suggest that men and women undergoing PCI have similar adjusted 2-year ischemic and bleeding outcomes, despite being characterized by different clinical presentation,” according to Valgimigli’s group.