No Reduction from Paracalcitol on Left Ventricular Mass in CKD Patients, but Other Outcomes Hint at Benefit

Forty-eight weeks of paracalcitol, the active hormonal form of vitamin D, doesn’t reduce left ventricular mass or most measures of cardiac function in patients with stage 3 or 4 chronic kidney disease (CKD), according to a study published in the Feb. 15 Journal of the American Medical Association. But there was one intriguing finding: treatment reduced left atrial volume and improved some clinical outcomes, setting the stage for larger studies to explore whether treatment with paracalcitol has a role in treatment of CKD patients.

“Cardiac hypertrophy is exceedingly common in patients with chronic kidney disease, both before and on dialysis,” according to Ravi Thadhani, MD, lead investigator and director for clinical research in nephrology at the Massachusetts General Hospital in Boston. CKD patients are “profoundly deficient” in vitamin D, and observational studies and animal models have suggested that vitamin D might reduce left ventricular hypertrophy. It was that hypothesis that Thadhani and colleagues set out to test in the study. He chose to use paracalcitol, rather than the dietary form of vitamin D, because the conversion to the hormonal form takes place in the kidneys, and is impaired in CKD.

The primary endpoint in the study was left ventricular mass index (LVMI) as determined by cardiac MRI, “the gold standard,” Thadhani said. Prespecified secondary endpoints included changes in diastolic mitral annular relaxation velocity (E’), changes in B-type natriuretic peptide (BNP), and several measures of left ventricular function. The trial, known as PRIMO (Paracalcitol Capsule Benefits in Renal Failure-Induced Cardiac Myopathy) was investigator-initiated, and funded by Abbott Laboratories.

The study took place at 60 centers in 11 countries, which required a coordination and standardization effort Thadhani characterized as “very labor-intensive.” It enrolled 227 patients, with a mean age of approximately 65. Most patients had hypertension, and many were receiving medication for it. Patients were randomized to receive either placebo or paracalcitol for 48 weeks. Early and sustained reduction in parathyroid hormone levels in the active-treatment group indicated good compliance throughout the study.

At the study’s end, there was no significant difference between the treatment arms in LVMI, even after a sensitivity analysis to account for patients with missing data or those lost to follow-up. While unexpected, Thadhani said, “I think it is an important result, because it gives us an idea of where the signal may not be,” and therefore will guide the design of future studies. There was also no difference in E’, a measure of left ventricular relaxation.

There were, however, clear differences between the groups on other secondary endpoints. B-type natriuretic peptide increased in both groups, but favored active treatment. While total hospitalizations did not differ between groups, there was only one cardiovascular event requiring hospitalization in the active treatment group, but eight in the placebo group, five of them for congestive heart failure.

Perhaps most intriguingly, there was a significant reduction in left atrial volume in patients receiving paracalcitol compared to placebo-treated patients (p=0.003), with the change occurring gradually and steadily over the 48 weeks. This outcome measure was not prespecified but instead was exploratory, Thadhani noted, “so we have to be cautious. But all together, the hospitalizations, the BNP, and the left atrial volume begin to define a treatment signal pointing to diastolic function.” The change in atrial volume was not accompanied by any changes in blood pressure.

“What we think is happening is that the drug is allowing better relaxation during diastole, therefore allowing the heart to have a stronger squeeze. The heart’s ability to relax is better, and as a result its ability to pump is better. The signal is a functional, rather than structural, change.” He noted that animal studies suggested this effect from paracalcitol as well.

“We are cautiously optimistic that we have a signal, one that could explain the outcomes. It was not the signal we were expecting, but one could argue that we could not plan a larger study without knowing where the signal lay, and now we have that better understanding.” Planning for a larger trial is now underway. Thadhani noted that if the effect on atrial relaxation is confirmed, it would make paracalcitol unique among cardiac drugs, most of which reduce blood pressure as they relax the heart.

Thadhani cautioned that therapy with paracalcitol was associated with more episodes of elevated calcium, and that paracalcitol, like other agents that activate the vitamin D receptor, can elevate serum creatinine without changing glomerular filtration rate. “Clinicians need to be aware of these two consequences of the therapy,” he said.

Reference

1.Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, Bhan I, Agarwal R, Zoccali C, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA 2012; 15:674–84.


March 2012 (Vol. 4, Number 3)