FDA is working to close the gap in developing CVD treatments

Ask the Expert Blog Series: Cardiovascular Disease – Heart Failure

BY Lazar Mandinov, Senior Medical Director, Parexel - 9.30.19 -

Lazar Mandinov, M.D., Ph.D., is a Senior Medical Director within Parexel’s Global Medical Services division.

A board-certified physician, Lazar has more than 15 years of experience in internal medicine, cardiology and interventional cardiology, with extensive expertise in coronary and structural heart interventions, heart failure, heart transplantation, hypertension, angiogenesis, coronary restenosis and stent thrombosis, cell biology, inflammation, and animal disease models.

Dr. Mandinov joined the medical device and pharmaceutical industry 15 years ago and has served as a medical technology executive with broad experience in clinical and medical affairs.  Through his work, Dr. Mandinov has been involved in the development of several compounds and cardiovascular disease (CVD) projects that have put Parexel at the forefront of this research in the life sciences industry. In recognition of World Heart Day, he shared his personal perspective on Heart Failure (HF), a CVD that occurs when your heart muscle doesn't pump blood as well as it should, the prevalence of the disease today, new advancements in HF treatment, and how Parexel is working to improve the outlook for patients facing HF and other CVDs.

Today there are just over 1,200 industry-sponsored active clinical trials for CVD[1].  While the number of CVD trials and therapies in development lags behind those of other therapeutic areas, the U.S. Food and Drug Administration (FDA) is working to spur advances in CVD treatments.  In fact, last July, the FDA held a workshop focused on the identification of potential clinical trial endpoints related to symptoms or physical function that could be of clinical importance in HF, resulting in the issuance of a draft guidance, Treatment for Heart Failure: Endpoints for Drug Development.

Progress such as this in CVD is incredibly important, and something we must continue.  To this end, on World Heart Day, it is important to acknowledge the significant impact of CVD, the progress that has been made in CVD treatments, and the work left to be done.

Significance of Cardiovascular Disease (CVD)

The global epidemiology in the 20th century is characterized by a fall in deaths and disability from communicable, or infectious diseases, such as malaria, hepatitis, etc., and an increase in noncommunicable, or chronic diseases (NCDs), such as heart attacks, cancer, etc., with CVD being the leading cause of mortality and morbidity in almost every region in the world.  To combat this trend, in 2013, the World Health Organization (WHO) launched the 25×25 Global Action Plan, an ambitious road map for countries to reduce NCD-related premature mortality by 25 percent by 2025. 

The global action plan focuses on strengthening health services and public policy to prevent and manage four major NCDs - CVD, cancer, diabetes mellitus, and chronic respiratory diseases - which contribute most to global morbidity and mortality. 

Of these 4 diseases, CVD deaths are among the most amenable to rapid change, suggesting that if the ambitious target is to be achieved, it will be necessary to reduce CVD deaths by more than 25 percent.  Heart failure (HF), as a consequence of ischemic heart disease, hypertension, cardiomyopathy/myocarditis, valve disease, etc., contributes significantly to disease burden.

The Impact of Heart Failure (HF)

HF, a condition which causes the heart to not pump blood as well as it should, is increasing in prevalence globally and is associated with considerable mortality and healthcare costs. An estimated 40 million people are living with HF globally.  Within the USA alone, an estimated 6 million individuals live with HF and 870,000 new cases are diagnosed every year. Prevalence increases steeply with age, and this burden is expected to exceed 8 million by 2030.  More than one million people are getting hospitalized annually due to HF.

Further, HF presents significant economic burden.  HF hospitalizations are associated with enormous health care expenditures as they were found to be the main cost driver to the total health care cost of HF.  Accurate estimates for the global financial burden of HF are challenging but were around US$108 billion in 2012.  The total medical costs in the US is predicted to rise from US$30 billion to almost $70 by 2030.  The highest-expenditure patients were found to have more comorbidities and higher inpatient mortality.

Data from the Global Burden of Disease Study indicate that approximately 17.3 million people died from cardiovascular causes in 2013, which is a 41% increase from the number of deaths attributed to CVD in 1990.  The increase in CVD burden is primarily due to demographic shifts, namely an expanding and ageing global population. However, mortality declines in HF have been documented. 

Although a diagnosis of HF portends increased mortality and loss of quality-adjusted life years, advances in evidence-based therapies including implementation of angiotensin-converting enzyme inhibitors, β-blockers, coronary revascularization, implantable cardioverter-defibrillators, and cardiac resynchronization therapeutic strategies, and the quality of care in the modern era have substantially improved outcomes for patients.  Nevertheless, 1 in 9 deaths in the United States, or almost 300, 000 deaths per year, are related to HF.

Treatment Challenges in HF

Patients with HF have an unpredictable trajectory with frequent exacerbations followed by relative improvement in symptoms.  One of the major challenges is to identify HF worsening before there is a need for emergency hospital admission.  International guidelines recommend disease management programs with education and support for individuals and families who wish to become more skilled in self-monitoring and management to identify decompensation early and support adherence to lifestyle and medication. 

Recent technological advances have allowed increasingly sophisticated attempts to remotely monitor and manage HF.  Simple, phone call based, remote assessments; standalone home-based systems; and now wearable technologies and implantable monitoring devices have opened a world of possibilities. 

It is not difficult to collect data remotely, but it has been a challenge to find a way to integrate such potentially continuous data streams into systems of care, and to convert more data into better decision-making that improves the outcome or experience of care.  The data streaming options impact the clinical research as well.  The design of clinical studies to robustly assess impact on clinically important outcomes, patient experience, workflow and cost is evolving, as is the framework of regulators and reimbursement authorities.

Promising Advancements in New Treatments

Significant advancements in the development of new therapies to treat certain diseases, such as diabetes, show great promise in reducing HF or CV death.

Specifically, Sodium glucose cotransporter 2 (SGLT2) inhibitors have been developed as treatment for diabetes due to their unique mechanism of action leading to excretion of glucose in the urine and subsequent lowering of plasma glucose independently of β-cell function.  The Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial of empagliflozin, lowered major adverse cardiovascular events (MACE), the composite of cardiovascular (CV) death,  MI and stroke, by a modest, albeit statistically significant 14%.  Unexpectedly, this trial also demonstrated a significant 38% reduction in CV death and a 32% fall in all-cause death.

Although the precise molecular mechanisms mediating the reduction in adverse cardiovascular outcomes of SGLT2 inhibitors have not been fully defined, their principal beneficial action appears to result from blockade of the reabsorption of glucose and sodium from the glomerular filtrate by the proximal tubule, leading to their excretion into the urine.  This action reduces extracellular fluid volume, which in turn increases hematocrit and lowers cardiac preload, afterload, arterial stiffness, blood pressure and left ventricular mass.

Just a few weeks ago the results from the phase 3, placebo-controlled DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) were presented at the ESC meeting in Paris, France.  A total of 4,744 patients with NYHA class II -IV HF and an ejection fraction less than 40% were randomly assigned to receive either dapagliflozin 10 mg once daily or placebo, in addition to recommended therapy.  There was a 26% reduction in the composite of worsening heart failure or cardiovascular death in patients on dapagliflozin. Death from cardiovascular causes occurred in 9.6% of patients on dapagliflozin and 11.5% in those on placebo, which presented 18% reduction.

As we look at where we are today with HF and CVD more broadly, it’s important to recognize the prevalence of these diseases, the research that is being done, and the work we have left to do.  It is my hope that by 2025 NCD-related premature mortality will be reduced by 25 percent, as WHO has set out to do.  We can all support this effort by taking the steps to reduce risk for NCDs. 

 


[1] Trialtrove access 24 September 2019


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