Uncovering novel approaches in heart failure science
The Late-Breaking Science session “Breakthrough Strategies in the HF Journey” on Saturday found that:
· CRISPR-Cas9 gene therapy is safe in Phase I transthyretin amyloidosis cardiomyopathy trial.
· Decision support in the emergency department improves access to heart failure (HF) care.
· Routinely collecting patient-reported outcomes and sharing them with clinicians can improve HF care.
· IV Iron can reduce HF rehospitalization, CV death in nonhospitalized HFrEF.
First-in-human CRISPR-Cas9 gene therapy safe, potentially effective in transthyretin amyloid cardiomyopathy
The first human trial of a CRISPR-Cas9 gene editing therapy has shown good safety and potential for significant clinical efficacy in a phase 1 trial of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM is caused by progressive accumulation of misfolded transthyretin (TTR) protein, which is produced almost exclusively in the liver, said Julian Gillmore, MD, PhD, professor of medicine at the University College London and head of UCL Centre for Amyloidosis in London. Investigational agent NTLA-2001 was designed to knock out the TTR gene in the liver of patients with ATTR amyloidosis, thereby halting production of TTR protein and progression of cardiomyopathy from accumulation of amyloid in the heart.
“Without treatment, amyloid deposits continue to accumulate in the heart and the condition is universally fatal,” Dr. Gillmore said. “The principle of treatment is to reduce the concentration of circulating TTR protein, reducing the amyloid substrate, to allow an equilibrium in which existing amyloid deposits are cleared more rapidly than new amyloid is deposited.”
The fact that the TTR protein is directly responsible for the disease coupled with the exclusive production of circulating TTR by the liver make ATTR amyloidosis a good target for in vivo gene editing using a CRISPR-Cas9 system, Dr. Gillmore noted. The normal function of TTR is limited to thyroxine and vitamin A transport, and experience with gene silencers indicate that knockout is likely to have limited and manageable adverse physiologic effects.
NTLA-2001 uses a lipid nanoparticle encapsulating messenger RNA for SpCas9 protein and a guide RNA that targets TTR. Preclinical studies showed durable knockdown of circulating TTR protein after a single dose. Nonhuman primate studies suggested a maximum human dose of 1 mg/kg.
Part 1 of this ascending dose trial included 12 patients with ATTR-CM. Six patients in NHYA functional class 1-2 received either 0.7 mg/kg or 1 mg/kg NTLA-2001 by intravenous infusion and six with NYHA class 3 heart failure received 0.7 mg/kg. Patients have been followed up to six months.
“NTLA-2001 was generally well tolerated, and no clinically significant laboratory findings were noted,” Dr. Gillmore reported. “TTR knockdown was very impressive. Serum transthyretin levels fell by more than 90% in all three cohorts such that there is a significant chance that we will see clinical benefit with patients achieving an equilibrium between amyloid production and clearance resulting in stability or possibly even improvement in cardiomyopathy symptoms.”
Many patients who present to the emergency department with heart failure symptoms are routinely hospitalized, either because there are no practical options for rapid outpatient care or uncertainty about their risk status. A novel decision-support algorithm reduced all-cause death and cardiovascular hospitalization compared to usual care at both 30 days and 20 months after initial presentation.
The Comparison of Outcomes and Access to Care for Heart Failure (COACH) Trial used the validated EHMRG30-ST risk algorithm based on information routinely available in electronic medical records to stratify HF patients presenting to the emergency department by lower and higher risk. High-risk patients were admitted for treatment. Low risk patients were referred to a rapid response outpatient clinic staffed with cardiologists and HF specialists.
“When patients go the emergency department currently, the physicians are using their clinical judgment to decide whether to admit them for heart failure or not,” said Douglas S. Lee, MD, PhD, FRCPC, Ted Rogers Chair in Heart Function Outcomes at the Peter Munk Cardiac Centre of the University Health Network and professor of medicine at the University of Toronto. “There are other factors as well, the patient’s social circumstances and support, among others, but it ultimately comes down to our clinicians’ judgment, which we think is pretty good. What we found was the COACH model can enhance outcomes. We saw better clinical outcomes, fewer high-risk patients released from the emergency department and faster outpatient follow-up among lower risk patients discharged early from hospital.”
COACH randomized 2,480 patients to the COACH intervention and 2,972 to conventional emergency department care across 10 acute care hospitals. The median age of patients was 78 and 55% were male.
At 30 days, the primary outcome of all-cause mortality and cardiovascular hospitalization was significantly lower in the intervention group (HR=0.880, p=0.036) compared to usual care. Results at 20 months similarly favored the intervention group (HR=0.951, p=0.007).
Direct emergency or hospital discharge of high-risk patients was reduced from 28.1% in usual care to 18.9% in the intervention group (p=0.009). Low-risk patients in the intervention group received ambulatory care more quickly than usual care patients (HR=1.127, p=0.028).
“We’d like to see clinicians use this decision-support tool in the emergency department to help make better decisions,” Dr. Lee said. “We’d also like to see if machine learning can’t improve the algorithm and outcomes and explore the effect of decision support on the total cost of care.”
COACH was published simultaneously in the New England Journal of Medicine.
Patient-reported outcomes can improve HF care
Initial results from the ongoing Patient-Reported Outcome Measurement in Heart Failure Clinic (PRO-HF) Trial show that routinely collecting a standardized questionnaire on heart failure health status during clinic visits can improve clinicians’ understanding of patients’ symptoms and patient experiences. There are also early indications that patient-reported outcomes can help clinicians better individualize HF management approaches.
“Understanding how heart failure symptoms affect a person’s life is crucial for the management of health failure patients,” said Alexander Tarlochan Singh Sandhu, MD, MS, cardiologist at Stanford University School of Medicine in Palo Alto, CA. “Traditionally health status assessment is done by clinicians using the New York Heart Association (NYHA) functional assessment classification. But clinicians are not particularly good at identifying a patient’s NYHA class and they make judgments regarding a patient’s symptom burden that are often discordant with patient’s own assessment of their health status.”
Researchers at the Stanford Heart Failure Clinic randomized 1,248 patients who completed a 12-question short form Kansas City Cardiomyopathy Questionnaire, the KCCQ12, at each clinic visit. KCCQ12 results were shared with clinicians for 624 patients in the intervention arm while KCCQ12 were not shared with clinicians treating the other 624 patients in the usual care arm.
As part of the trial, the researchers evaluated clinician assessment of health status and patient experience among the subset of 1,051 patients with their initial PRO-HF clinic visits between October 2021 and June 2022. The researchers compared the accuracy of clinicians’ NYHA assessment by comparing clinician assessment with KCCQ-12 responses in both arms. They also evaluated patient’s assessment of clinician interactions and interviewed clinicians regarding the usefulness of KCCQ12 results and the effects on management decisions. All trial participants will be followed a total of 12 months following enrollment.
The initial results, based on patients’ initial clinic visits, showed that correlations between NYHA class and patient-reported health states were significantly stronger when clinicians had access to patients’ KCCQ12 overall summary scores, r=-0.73 vs r=-0.061 (p<0.001). Patients in the intervention arm were more likely to agree that their clinicians understood their symptoms (OR=2.16) and their overall health status (OR=2.10).
“We are seeing real evidence that implementing patient-reported health status assessment as a part of routine heart failure care in the outpatient setting can improve clinicians’ assessment of patients’ health status and improve patients’ evaluations of their clinicians and the care they receive,” Dr. Sandhu said. “Identifying symptomatic patients more accurately is increasingly important for treatments in which the primary benefit is improved quality of life and improved functional status.”
PRO-HF was published simultaneously in Circulation: Heart Failure.
IV ferric derisomaltose reduces HF rehospitalization and CV death for a broad range of ambulatory and hospitalized patients
New data show that intravenous ferric derisomaltose (FDM) reduces the risk of recurrent HF hospitalization and cardiovascular death by up to 24% in a broad population of patients with heart failure with a reduced left ventricular ejection ≤45% (HFrEF) fraction and iron deficiency. About 85% of patients were not hospitalized at randomization.
Up to 50% of heart failure patients are iron deficient, noted Paul R. Kalra, MD, FRCP, at Portsmouth Hospitals University NHS Trust, Portsmouth, and University of Glasgow, U.K., although many are not anemic. Iron deficiency is associated with worse quality of life, impaired exercise capacity and a greater risk of both HF hospitalization and cardiovascular death.
“We know from earlier trials that for patients with HFrEF, intravenous ferric carboxymaltose (FCM) improves symptoms and exercise capacity in the following three to six months,” Dr. Kalra said. “For patients hospitalized with HFrEF, IV FCM reduced the risk of recurrent rehospitalization for heart failure over 12 months.
“IRONMAN enrolled a much broader population of patients with HFrEF, mostly from outpatient clinics, and followed their outcome for up to 5 years. This long follow-up revealed the high burden of disease and current unmet need of this population as well as the benefits and safety of IV FDM, despite the latter part of the trial being severely affected by COVID-19.”
IRONMAN randomized 1,137 patients with HFrEF and evidence of iron deficiency to intravenous FDM or usual care between 2016 and 2021 across 70 hospital clinics in the United Kingdom. The primary endpoint was a composite of recurrent HF hospitalizations and cardiovascular death. Secondary endpoints included quality of life. Median follow-up was 2.7 years.
Overall, there was an 18% reduction in the primary endpoint (p=0.07) for patients in the iron arm. A pre-specified COVID-19 sensitivity analysis, 91% of the total cohort, showed a 24% reduction in the primary endpoint (p=0.045). Secondary endpoints showed trends favoring IV FDM, although most did not achieve statistical significance.
The trial was analyzed by intention-to-treat, but 17% of patients randomized to the control arm received non-protocol IV iron, Dr. Kalra said. He cautioned that this out-of-protocol iron treatment may have affected differences between treatment and usual care arms.
“IRONMAN adds substantially to our knowledge of the efficacy and safety of intravenous iron for patients with heart failure, with no evidence of an excess of adverse events,” Dr. Kalra said. “These results are likely to influence clinical practice and guidelines in Europe and North America.”
IRONMAN was published simultaneously in The Lancet.