Kevin Kunzmann

The US Food and Drug Administration (FDA) has approved evolocumab (Repatha) injection as an adjunct to diet or other treatment for patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).

, the new approval expands the indicated use of evolocumab, which was previously approved as an add-on therapy for reducing LDL-C in adults with HeFH and patients with HoFH.

The approval granted to Amgen was based on findings from a pair of pediatric clinical trials. The first, involving patients aged 10-17 years with HeFH, assessed 420 mg monthly subcutaneous injection for 24 weeks; patients reported a mean 38% reduction in LDL-C versus placebo.

In the second trial, patients aged 11-17 years old with HoFH received the same evolocumab dose regimen for 80 weeks, and reported a mean 14% reduction in LDL-C compared to baseline.

Evolocumab previously received orphan drug designation from the FDA in 2013 to treat HoFH. It is not indicated for use in patients with serious hypersensitivity, either by clinical diagnosis or emerging signs or symptoms.

Approximately 1 in 250,000 individuals are diagnosed with HoFH, while HeFH is prevalent in 1 in every 250 individuals. The conditions are rare and life-threatening, characterized by gene mutations that influence the body’s clearance of cholesterol including LDL-C.

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Announced on September 24, the approval is for use as an adjunct to diet and other LDL-C-lowering therapies for reducing LDL-C in patients aged 10 years and older with heterozygous familial hypercholesterolemia.



Evolocumab Approved for Pediatric Patients with Heterozygous Familial Hypercholesterolemia

One of the most prominent discussions occurring at The Metabolic Institute of America’s (TMIOA) 2021 5th Heart in Diabetes sessions in New York, NY, centered around subpar uptake of newer medications, among endocrinologists, cardiologists, and other providers. 

Much of this discussion was related to advancing role of SGLT2 inhibitors and GLP-1 receptor agonists in the treatment of patients with diabetes and other cardiometabolic conditions, such as chronic kidney disease and heart failure.

This role, Matthew Budoff, MD, explained, is one that is being stalled by regulatory processes. In the second segment of an interview with our sister publication 

 at the meeting, Budoff, professor of medicine at David Geffen School of Medicine at UCLA, explained why the real-world uptake of newer cardiometabolic agents lags behind despite proven efficacy in clinical trials.

In this interview, Budoff explained, the US operates on a “general rule” that findings from 2 randomized trials may constitute a class I indication for a drug class. For example, he said, the DAPA-HF and EMPEROR trials supported the use of SGLT2 inhibitors for the reduced risk of heart failure in patients with and without diabetes. Budoff cited the CANVAS and EMPA-REG trials as supporting the drug class’ benefit in reducing composite cardiovascular death in patients with diabetes and atherosclerotic cardiovascular disease. Budoff went on to cite a trio of randomized clinical trials support GLP-1 receptor agonists for the reduction of composite coronary events, stroke, and all-cause death, he said.

For more on this topic, check out the video interview below:


Videos

Matthew Budoff, MD, discusses what he views as hurdles to achieving optimal prescription of newer agents in the treatment of cardiometabolic conditions, including diabetes, heart failure, dyslipidemia, and more. 

Matthew Budoff, MD: Need for Greater Uptake of Newer Medications

This article was originally published on 


The US Food and Drug Administration (FDA) has approved treprostinil (Tyvaso) Inhalation Solution for the treatment of patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD) to help improve exercise ability.

The indication is the second granted by the FDA for the United Therapeutics drug, following its approval as a pulmonary arterial hypertension (PAH) therapy in July 2009.

This supplemental New Drug Application (sNDA) for treprostinil was supported by data from the INCREASE trial, currently considered the largest and most comprehensive completed study of adult patients with PH-ILD.

The randomized, double-blind, placebo-controlled, parallel-group, 16-week trial involved 326 patients from multiple care centers. Investigators reported outcomes including significant improvement in PH-ILD adult patient six-minute walk distance (6MWD) when treated with treprostinil, as well as improvements among patients with differing PH-ILD etiology, disease severity, age, gender, baseline hemodynamics, and dose differences for treatment.

Investigators also reported significant patient improvements in secondary endpoints including reduction in NT-proBNP, time to first clinical worsening event, change in peak 6MWD at week 12, and change in trough 6MWD at week 15.

Patients additionally benefitted in placebo-corrected forced vital capacity (FVC) improvements, and reported significantly fewer underlying lung disease exacerbations. A treoprostinil dose of 12 breaths per session, 4 times daily, was well-tolerated and associated with a safety profile consistent in previous trials.

Pulmonary hypertension is estimated to affect at least 15% of patients with early-stage ILD, which is characterized as scarring in the lungs from a series of varied diseases. There are approximately 30,000 PH-ILD patients in the US.

As Aaron Waxman, MD, PhD, Director of the Pulmonary Vascular Disease Program at Brigham and Women's Hospital and the chair of the INCREASE Study Steering Committee, said in a 

, adults living with PH-ILD generally experience a poorer quality of life, increased shortness of breath, poor exercise tolerance, and higher risk of mortality.

“Until now, clinicians treating these patients did not have any approved treatment options," Waxman said. "The regulatory approval of Tyvaso, an inhaled treatment, is exciting news both for patients with PH-ILD and the physicians who treat adults living with this serious, life-threatening disease. This will change the way we manage these patients."

Martine Rothblatt, PhD, chairperson and chief executive officer of United Therapeutics, called the sNDA approval a “landmark treatment advancement” for the PH-ILD population.

"It also underscores our commitment to driving innovation in the field of pulmonary hypertension and expanding the number of patients who can achieve a clinical benefit from Tyvaso,” Rothblatt said. “We plan to tap into our experience and expanded infrastructure to bring this safe and effective inhaled therapy to the many patients living with PH-ILD in the United States."

The US FDA has granted a second approval to treprostinil (Tyvaso) inhalation solution, this time for the treatment of patients pulmonary hypertension associated with interstitial lung disease (PH-ILD) to help improve exercise ability.

Treprostinil (Tyvaso) Receives FDA Approval  for Pulmonary Hypertension Linked to Interstitial Lung Disease

Findings from a new study suggest placement of an inferior vena cava (IVC) filter was linked to significant decreases in mortality and pulmonary embolism risk among cancer patients with 


A population-based cohort analysis conducted by a team of Texas-based investigators, results indicated IVC filter placement could help mitigate the increased risk of fatal pulmonary embolism in patients with cancer.

Investigators, led by Samyuktha Balabhadra, MD, of the Department of Radiology at the University of Texas Health McGovern School of Medicine, sought to understand the appropriate use of IVC filters in patients with cancer by evaluating associations between the devices and pulmonary embolism development among cancer patients with DVT.

“This knowledge gap in IVC filter utility and outcomes is even more pronounced for patients with cancer because very few studies have investigated this patient population, to our knowledge,” they wrote. “Defining the appropriate use of IVC filters in patients with cancer remains a substantially unmet clinical need.”

Their assessment included administrative data on 88,585 patients from state inpatient databases for California and Florida, ranging in years from 2005-2014.

Balabhadra and colleagues identified patients with cancer and acute lower extremity DVT through diagnostic and procedure codes. The team evaluated subsequent hospital visits among eligible patients for the placement of an IVC filter, new embolism development, new DVT development, and in-hospital mortality.

Pulmonary embolism-free survival was measured from initial DVT diagnosis date until the development of pulmonary embolism. In the event that a patient received a pulmonary embolism diagnosis at the same time as their initial DVT diagnosis, they were considered to not have developed a new pulmonary embolism.

Median patient age was 71 years old, with half (50.8%) being male. Patients were analyzed across 534,623 inpatient encounters, with a median follow-up time of 479 days.

Of the cohort, 33,740 patients (38.1%) underwent IVC filter placement—most (80.4%) occurring within 30 days of initial DVT diagnosis. Patients with comorbid risk factors including upper gastrointestinal bleeding, intracranial hemorrhage, and coagulopathy were at 32%, 21%, and 9% greater odds of receiving a filter, respectively.

A new pulmonary embolism developed in 5.1% of IVC filter-recipient patients after their initial DVT diagnosis.

Investigators observed a 31% improvement in pulmonary embolism-free survival among these patients than those who did not receive an IVC filter—even after propensity score matching and competing risk analysis (HR, 0.69; 95% CI, 0.64-0.75; 

 <.001).

IVC filter placement additionally reduced pulmonary embolism development risk among patients with very high-risk, high-risk, and low-risk malignant neoplasms.

Despite previous analyses, investigators did not observe an association between IVC filter placement and increased new DVT development risk, with account for patient anticoagulation use and imbalanced risk factors.

That said, Balabhadra and colleagues stressed the potential risk of IVC filter placement, as per communications from the US Food and Drug Administration (FDA) in 2014 and 2010 on their link to device migration, penetration, and embolization.

“The most common complication associated with IVC filters, however, is an increased incidence of DVT,” investigators wrote. “As the devices themselves represent foreign material within a blood vessel, they are to some extent thrombogenic and can lead to thrombus formation and propagation.”

Nonetheless, the team concluded that, when accounting for death as a competing risk and comorbidities by propensity score matching, IVC filter placement in cancer patients with DVT was linked to significantly reduced new pulmonary embolism.

“These data suggest that IVC filter use in patients with cancer is of potential benefit in appropriately selected patients, and that further investigations into the appropriate use of these devices is warranted,” they wrote.

The study, “

Association of Inferior Vena Cava Filter Placement With Rates of Pulmonary Embolism in Patients With Cancer and Acute Lower Extremity Deep Venous Thrombosis

New research suggests IVC filter placement could attenuate the risk of pulmonary embolism in patients with cancer-related DVT. 

IVC Filter Could Cut Pulmonary Embolism Risk in Cancer-Related DVT

How ACE2 Reduction Associated with Aging Affects COVID-19 Severity,

" was originally published on our partner site 

A new perspective from a team of Maryland-based cardiovascular clinicians sheds insight on an often forgotten facet of the inherent COVID-19 risk carried by patients with cardiovascular history: the decline in angiotensin-converting enzyme 2 (ACE2) expression associated with aging, and the response of care most common in such patients.

In an essay published Friday morning, a trio of investigators-Majd AlGhatrif, MD, MA; Oscar Cingolani, MD; and Edward G. Lakatta, MD; of Johns Hopkins School of Medicine, the National Institute on Aging and National Institutes of Health-called for the urgent expansion of renin-angiotensin system (RAS)-based intervention assessment as part of the need for clinical understanding as to how lung complications are driving novel coronavirus (COVID-19) mortality worldwide.

As the team noted, ACE2 is not only prevalent in the pathogenesis of COVID-19, but is part of RAS signaling. Though data is scarce on the topic, it is known now that ACE2 is both targeted by SARS-CoV-2 in its entrances to cells and a critical player in anti-inflammation during RAS signaling-converting angiotensin II to angiotensin 1-7.

The age-associated decrease of ACE2 expression, which investigators have observed in the lungs of rats, is in line with “a constellation of major proinflammatory changes perpetrated by an age-associated increase in RAS signaling throughout the body,” the team wrote.

Such proinflammatory profiles are featured in patients with hypertension and diabetes-a pair of diseases highly common in older patients.

The increase of ACE2 in such patients with ACE inhibitors and angiotensin receptor blockers (ARBs) presents a paradox to investigators: how can ACE2 reduction in older, cardiovascular-risk patients put them at greater risk of COVID-19 severe symptoms when ACE2 is the gateway for the disease into cells?

The team pointed to data procured from the severe acute respiratory syndrome (SARS) epidemic of 2003, which most prominently affected persons in their 30s and 40s-despite these younger patients reporting lower disease severity and risk of mortality versus older people with pre-existing conditions.

“Similarly, in the COVID-19 pandemic, it is plausible that greater expression of ACE2 leads to higher predisposition to incur the disease,” they wrote.

Preliminary epidemiologic data from South Korea-the country with the greatest rate of population-wide testing for the disease-shows that younger adults are reporting the greatest rate of infection, despite perceived higher ACE2 levels. COVID-19 severity, however, has been observed in older patient populations, such as that of Italy’s.

“Hence, compared with young individuals, older persons with (cardiovascular disease) who already have reduced ACE2 levels will be expected to be more predisposed to exaggerated inflammation with further reduction in ACE2 expression in the context of COVID-19, manifesting with greater disease severity,” they explained.

The team hypothesized that SARS-CoV-2 binding to ACE2 creates an acutely exaggerated proinflammatory background, thereby predisposing older adults with hypertension and diabetes treated with ACE inhibitors and ARBs to correct ACE2 levels at a greater risk of disease severity and mortality.

This belief, they wrote, aligns with evidence of angiotensin II antagonists benefitting sepsis-associated acute lung injury.

Going forward, the team advised that clinicians continue treating patients with ACE inhibitors and ARB and pursue clinical investigations that consider RAS interventions for COVID-19 severity reduction.

The Dilemma of Coronavirus Disease 2019, Aging, and Cardiovascular Disease

Why Older Patients Are More At Risk for COVID-19 : A Decline In ACE2 Expression

This article was originally published online by Practical Cardiology's sibling publication, 

New pooled data from a trio of pivotal phase 3 trials assessing novel investigative drug inclisiran, which were presented at ACC 20, demonstrate Novartis's first-in-class siRNA drug inclisiran provided significant and durable benefit for LDL cholesterol (LDL-C) reduction in patients with atherosclerotic cardiovascular disease (ASCVD).

The ORION trial program now includes new data pooled from ORION-9, -10, and -11 showing reduction in LDL-C of 51% when used in addition to other lipid-lowering therapies (LLT) over 17 months of treatment.

A prespecified exploratory analysis using safety from the 3 trials also indicated fewer major adverse cardiovascular events (MACE) with inclisiran (7.1%) versus placebo (9.4%).

Patients treated with inclisiran also reported good tolerance, with a safety profile similar to placebo. The most common adverse reactions reported to occur in ≥3% of treated patients and more frequently than those with placebo included: diabetes mellitus; hypertension; nasopharyngitis; arthralgia; back pain; dyspnea; bronchitis; and upper respiratory tract infection.

The novel, first-in-class drug is initially administered subcutaneously, again at 3 months, and then again every 6 months. It has potential to become the first and only LDL-C-lowering treatment in the siRNA class marketed for use in the US.

In a special edition DocTalk podcast interview with 

HCPLive®—Practical Cardiology's sibling publication—

ORION-11 principal investigator Kausik Ray, MD, of the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, discussed the newest inclisiran findings, what the marketed potential of the therapy is as it has been currently assessed, and what future research will entail.

Ray also shared planned to assess the therapy’s benefit for pediatric patients, homozygous familial hypercholesterolemia (HoFH) benefits, and the reduction of cardiovascular outcome risks. These, plus a currently-planned extension trial, will take the ORION program research into 2024.

“All these patients in ORION-9, -10, and -11 will now go into to an open-label extension program,” Ray said. “And that’s ORION-8, and that will report out in several years’ time.”

Results of a pooled analysis of trials from the ORION program offer further insight into the effects of inclisiran on LDL-C in patients with atherosclerotic cardiovascular disease.