Nanomaterials are materials in which
50% or more of the contained particles are in the range of 1 nm to 100 nm. They
have several potential clinical applications, including antithrombotic therapy,
cell therapy, treatment of atherosclerosis, drug delivery, and nanorods for
induction of angiogenesis. Sanjay Misra, MD, Mayo Clinic, Rochester, Minnesota,
USA, discussed the targets and therapies of nanotechnology.
Karagkiozaki et al. [Int J Nanomedicine 2010] found that the surface
nanotopography of stent nanocoating influences the behavior of platelets, and
this is a key factor for biomaterial thrombogenicity. Patra et al. [Nano
Lett 2011] demonstrated that europium hydroxide nanorods (inorganic
nanorods) with a diameter of 35 nm to 50 nm and a length of 200 nm to 300 nm cause
an increase in proangiogenic cytokines, such as vascular endothelial growth
factor-A and basic fibroblast growth factor.
Various nanoscale technologies are being applied to the
field of stem cell therapy for the treatment of cardiovascular diseases. Other
promising applications include the prevention, imaging, and treatment of
atherosclerosis [Psarros C et al. Nanomedicine 2012] and the use of
copolymer-stabilized micro- and nanobubbles as vectors for the anticancer drug
doxorubicin [Rapoport N et al. J Natl Cancer Inst 2007]. Valenzuela and
Simon [Nanomedicine 2012] describe a micellar estradiol formulation that
serves as an alternative transdermal delivery system for hormone replacement
therapy. According to Dr. Misra, nanotechnologies have far reaching
implications for the practice of medicine in a wide range of fields.
Ventricular Assist Devices
Mark S. Slaughter, MD, University of Louisville, Louisville,
Kentucky, USA, presented information on next-generation ventricular assist devices
(VADs), heart valves, and other devices. All of the products he discussed are
in various stages of development, and none are FDA-approved.
As VAD technology evolves it is increasingly being applied as destination
therapy rather than exclusively as a bridge to transplant. Kirklin et al. [J
Thorac Cardiovasc Surg 2012] reported that the average 2-year survival
after cardiac transplantation is ~80%. However, evolution from pulsatile to
continuous flow technology has dramatically improved 1- and 2-year survival,
and important subsets of patients with continuous flow destination therapy now
enjoy survival that is comparable with heart transplantation out to 2
years. After discussing a breakthrough technology that delivers nitric
oxide from a novel liquid source, he said that new VAD technology should reduce
operative trauma, thus reducing overall adverse events.
Valves and Devices
Next-generation valve companies are making use of the small
intestine submucosa-extracellular matrix (SIS-ECM) to improve their products
and potentially improve postoperative outcomes. CorMatrix Cardiovascular is
testing tissue-engineered ECM for pericardial repair; the product comes from
SIS-ECM is obtained from the submucosa of the small intestine of pigs and
consists of a complex matrix of collagen; the submucose is found between the
mucosal and muscular layers of the small intestine. It provides strength to the
intestine and also serves as a reservoir for cytokines that support the growth and
differentiation of intestinal epithelial cells.
Transapical aortic valve implantation has evolved as a treatment option for
high-risk patients who have severe aortic stenosis. While much of the focus has
been on improving valves and the delivery systems, issues of vascular access
and safe closure remain important and of great interest.
Dr. Slaughter reported that a first-in-human clinical trial [NCT01721642] of
the Apica ASC transapical access and closure device had successful access and
closure, with no device-related complications to date.
Dr. Slaughter said that natural scaffolds that repopulate with native cells
might fix the problem of durability of bioprosthetic valves; that safe,
reliable, and near bloodless access to the LV apex could improve outcomes and
approach to both aortic and mitral valve replacements; that the ability to
deliver a predetermined dose of cells/matrix to a specific area could improve
clinical efficacy of regenerative medicine; and that new delivery systems for
nitric oxide could allow chronic treatment in patients who are not candidates
for other therapies.
Balloons and Bioabsorbable Stents
Bruno Scheller, MD, Universitätsklinikum des Saarlandes,
Homburg/Saar, Germany, focused on drug-coated balloons and bioabsorbable
stents—vascular restoration therapy, ie, the fourth revolution in
interventional cardiology, according to Wykrzykowska et al. [EuroIntervention2009].
Long-term (>10 years) clinical outcomes of a first-in-human study of a fully
biodegradable poly-l-lactic acid coronary stent found rates free of all-cause
death, cardiac death, and major adverse cardiac events at 10 years of 87%, 98%,
and 50%, respectively [Nishio S et al. Circulation 2012]. Intravascular
ultrasound data suggest that the stent struts mostly disappear within 3 years.
The external elastic membrane area and stent area did not change.
ABSORB Clinical Investigation, Cohort B [ABSORB B; NCT00856856], a multicenter,
single-arm trial, assessed the safety and performance of an everolimus-eluting
bioresorbable vascular scaffold [Ormiston JA et al. Circ Cardiovasc Interv2012]. Forty-five patients underwent serial invasive imaging at 6 and 24 months
of follow-up. Struts still recognizable on optical coherence tomography at 2
years showed 99% neointimal coverage with optical and ultrasonic signs of
bioresorption accompanied by an increase in mean scaffold area compared with
baseline. The 2-year major cardiac event rate was 6.8% without any scaffold
thrombosis, confirming the medium-term safety and efficacy of the new device.
However, randomized controlled clinical trials are missing for bioabsorbable
Drug-coated balloon catheters have been studied in a variety of randomized
studies and large registries, especially paclitaxel-iopromide- and
paclitaxel-urea coated balloons. For patients with peripheral artery disease, a
meta-analysis of randomized trials compared target lesion revascularization
using paclitaxel-coated balloon angioplasty versus conventional uncoated
balloon angioplasty showed superior antirestenotic efficacy compared with
uncoated balloon angioplasty (Table 1) [Cassese S et al. Circ Cardiovasc
Interv 2012]. Other studies in coronary arteries have had similar findings
in the treatment of in-stent restenosis and de novo lesions [Unverdorben M et
al. Circulation 2009; Wöhrle J et al. J Am Coll Cardiol 2012].
Dr. Scheller said that drug-coated balloons are not a replacement for
drug-eluting stents, but a new option in endovascular and coronary
interventions and potentially useful in areas of the leg where stenting is
typically avoided due to joint motion. Both drug-coated balloons and
bioabsorbable stents represent the technology for a new age of vascular therapy
that leaves no permanent implants behind.
1. Target Lesion Revascularization.
balloon; UCB=uncoated balloon. Adapted from Cassesse S et al. Paclitaxel-Coated
Versus Uncoated Balloon Angioplasty Reduces Target Lesion Revascularization in
Patients With Femoropopliteal Arterial Disease: A Meta-Analysis of Randomized
Trials, Circ Cardiovasc Interv 2012;5(4): 582-589.
Stephen MacMahon, MD, DSc, George Institute for Global Health at the University of Sydney, Sydney, Australia, presented the Lewis A. Conner Memorial Lecture. The theme of Prof. MacMahon’s presentation was frugal innovation, an approach he believes will be essential for the future of cardiovascular (CV) medicine in the 21st century. "Despite the many innovations in the treatment and prevention of cardiovascular disease [CVD], the benefits have been felt by few of the many individuals that are actually in need,” said Prof. MacMahon.
A major challenge today is how to provide basic care for the 7 billion people on the planet, 3 billion of whom are likely to develop serious CVD sometime in their life. Currently, 5 billion individuals have no reliable access to essential CV health care. In a study conducted in India, the prevalence of coronary heart disease (CHD) and cerebrovascular disease was estimated to be 4.8% and 2.0%, respectively. Among individuals with either diagnosis, 14% reported taking aspirin, 41% took a blood pressure-lowering medication, and only 5% reported using a cholesterol-lowering medication [Joshi R et al. Circulation2009].
Similar findings were reported in the Prospective Urban Rural Epidemiological [PURE] study, in which the use of secondary prevention medications was low worldwide but especially in low-income countries and rural areas [Yusuf S et al. Lancet2011]. Many people in the world with serious CVD receive no treatment whatsoever because most of the world’s high-risk individuals live in resource-poor regions. Of the individuals who are at risk of CVD, 80 million live in high-income regions and 250 million live in the rest of world. Those in the high-income areas have access to a CV drug budget of $100 billion compared with <$20 million in the poorer regions. The same disparity holds true for quality of care and the distribution of physicians. Cost is another major issue. In a study in China, workers without health insurance were 7 times more likely to experience catastrophic payments (defined as ≥30% of total household annual income) than workers with insurance [Heeley E et al. Stroke2009].
There are vast numbers of unmet CV healthcare needs that are related to inadequate workforce and resources. There is a great variation in the global quality of care and high cost relative to the ability to pay. Consequently, many tens of millions of individuals die prematurely and unnecessarily every decade from preventable CV causes. Radical action is needed to avert this consequence. Prof. MacMahon proposed the need to embrace the notion of frugal innovation, which includes solutions that are affordable to the >3 billion individuals living on less than $2.50/day. These innovations need to be economically disruptive and lead to fundamental market changes, ie, a model that is low margin, high volume.
Prof. MacMahon discussed three frugal innovation approaches that might help alleviate the unmet needs for CVD prevention and treatment.
Primary care workforce models developed in high-income countries are impractical and unaffordable elsewhere. Physician-centered care is not the solution as there are too few physicians, and they are too expensive, difficult to retain, and display a wide variation in the quality of care. For example, there are 500,000 doctors in India today; if India were to adopt a US-style approach to health care, 3 million physicians would be required.
To meet the demands of individuals in low-income regions, the medical workforce needs to be larger and more affordable, and deliver care with consistent quality. An alternative is to equip and train an allied work force to provide basic, essential cardiac care. In a government-funded program in India, high school graduates were trained to be multipurpose health workers. They were trained using an algorithm-based screening and treatment approach for secondary prevention and high-risk primary prevention of CVD, the leading cause of death in India. These workers were able to detect and identify high-risk individuals at a higher rate than physicians. There was also good agreement between the health workers and physicians regarding treatment of patients with CHD, ie, the prescribing of angiotensin-converting enzyme inhibitors, β-blockers, statins, and aspirin (Figure 1) [Joshi R et al. J Am Coll Cardiol 2012]. There is a similar program ongoing in China for patients at high risk of stroke.
Figure 1. Identification of High-Risk Individuals by Multipurpose Healthworker.
Adapted from S MacMahon, MD. AHA 2012.
Another approach is the development of low-cost technologies, in part to facilitate the expansion of the medical work force, but also to improve the quality of care. The Systematic Medical Assessment Referral and Treatment (SMART) program is an example of an electronic decision support system used for patient assessment, diagnosis, treatment, follow-up, referral, and quality control regarding primary and secondary prevention of stroke, heart disease, and kidney disease. Low-cost remote electronic sensors for mobile phones are being developed that can collect a range of information regarding CV markers, eg, blood pressure, heart rate, electrocardiogram, and heart sounds. Another technological development underway is consumer devices for monitoring CV risk, early warning signs, and symptoms. These devices also contain programs that remind patients to takemedication, keep track of weight loss, choose healthy foods, and schedule appointments.
Pharmaceutical innovation is particularly important for emerging markets. Low-cost drugs in fixed-dose once-a-day combinations can help meet the demands for drugs in low-income regions. This requires a shift to low margins with high volume. Efforts are underway to develop drugs that are low-cost, fixed-dose, once-a-day combinations for CVD. The Programme to Improve Life and Longevity [PILL] pilot study conducted by Prof. MacMahon was a 12-week placebo-controlled trial using a fixed-dose combination pill for stroke prevention [PILL Collaborative Group. PLoS ONE 2011]. The pill was a combination of aspirin (75 mg), simvastatin (20 mg), lisinopril (10 mg), and hydrochlorothiazide (12.5 mg) taken daily. The estimated effects for patients continuing long-term treatment of the combined pill produced included a ~60% reduction for risk of CHD and ischemic stroke (Table 1) at a cost significantly less than the sum of the individual ingredients.
Table 1. Estimated Reductions in Cardiovascular Risk for Those Remaining on Treatment.
Adapted from PILL Collaborative Group. An International Randomised Placebo-Controlled Trial of a Four-Component Combination Pill ("Polypill”) in People with Raised Cardiovascular Risk. PLoS ONE 2011;6(5): e19857.
Ongoing efforts like these have the potential to reduce the disease burden while preventing a sharp rise in worldwide costs.
LX4211, a dual inhibitor of sodium
glucose transporters 1 and 2 (SGLT1/2), demonstrated a clear dose reduction in
plasma glucose concentration (HbA1C) in patients with type 2 diabetes mellitus
(T2DM) inadequately controlled on metformin monotherapy in the Safety and
Efficacy of LX4211 with Metformin in T2DM Patients with Inadequate Glycemic
Control on Metformin study. SGLT1 is primarily responsible for gastrointestinal
(GI) glucose absorption, while SGLT2 is primarily responsible for renal glucose
reabsorption, leading to reductions in blood glucose levels and weight loss.
Julio Rosenstock, MD, Dallas Diabetes and Endocrine Center, Dallas, Texas, USA,
who presented this study believes that LX4211 has the potential to address
multiple cardiovascular disease risk factors in diabetic patients.
The study was designed to evaluate the dose-range efficacy and safety of LX4211
versus placebo from baseline to Week 12 in patients with T2DM inadequately
controlled on metformin monotherapy. Additional eligibility criteria included
being aged 18 to 75 years with a body mass index ≤45 kg/m2, and
HbA1C ≥7% to ≤10.5%. After 2 weeks of screening, subjects were randomly
assigned to treatment with placebo or 1 of 4 LX4211 dosages (75 mg QD, 200 mg
QD, 200 mg BID, or 400 mg QD) for 12 weeks and followed for an additional 2
weeks. The primary study endpoint was the change in HbA1C from baseline to Week
12. Secondary outcomes included percentage of patients reaching target HbA1C of
≤7% at Week 12, fasting plasma glucose change from baseline to Week 12, body
weight change, blood pressure (BP) change, urinary glucose change, and safety.
Randomized patients (n=299) were mean age 56 years, 42% female, and had a
BMI of 32 to 34 kg/m2, and HbA1C of 7.9% to 8.3 %. Patients had
normal blood pressure (BP) and lipid levels. All doses of LX411 significantly
reduced HbA1C compared with baseline, with dose related changes from 0.4% to
0.9%. Baseline characteristics were balanced between randomization groups.
Relative to placebo after 12 weeks of treatment; LX411 reduced HbA1C beginning
at Week 1 and continuing out to Week 12 (p<0.001 for the 200-mg BID and
400-mg QD doses; p<0.05 for 75-mg and 200-mg QD doses). Maximum effect on
urinary glucose excretion was achieved with 200 mg QD at Weeks 4, 8, and 12. No
further glucose excretion was achieved with the 200-mg BID or 400-mg QD doses.
However, further reductions in HbA1C were evident with the higher doses of
LX411, which probably indicates further inhibition of SGLT1. Weight loss was
achieved with all doses except for the 75-mg dose, up to 2.5 kg at Week 12 with
200 mg BID (p<0.001). Compared with placebo, systolic BP was significantly
(p<0.05) reduced with the 200-mg BID and 400-mg QD doses over the 12-week
period. Diastolic BP was not significantly changed. No clinically meaningful
changes in high- or low-density lipoprotein cholesterol levels over baseline or
compared with placebo were evident.
Adverse events (AEs) were well balanced across the treatment arms and similar
in frequency to those seen with placebo. Common AEs associated with LX4211 were
vaginal infections (3% to 5%), GI disorders, and headaches. There were no
dose-related differences in drug discontinuation due to AEs.
In poorly controlled patients with T2DM on metformin, dual SGLT 1 and 2
inhibition with LX2411 improved glucose control and was associated with
consistent reductions in systolic BP and body weight without an increase in
hypoglycemia. Dr. Rosenstock concluded that, because of its insulin-independent
effects, LX4211 can potentially address multiple cardiovascular risk factors in
patients with T2DM and it warrants further study.
All novel oral glycemic agents are now required to undergo Phase 3 study
evaluations to determine whether they affect clinical cardiovascular endpoints,
including heart failure and ischemic events. In addition, these Phase 3 trials
are often longer than the initial studies investigating glucose control and are
helpful to evaluate, serious AEs, such as hypoglycemia, hypotension, or
off-target effects. With this particular class of diabetic agents, an increase
in genitourinary infections may be plausible since glycosuria is increased with
Basic research has suggested that some individual vitamin and mineral components of multivitamins might reduce the risk of cardiovascular disease (CVD). However, no large-scale, long-term randomized trials have tested the effect of multivitamins. Howard D. Sesso, ScD, MPH, Brigham and Women’s Hospital, Boston, Massachusetts, USA, presented results from the Physicians’ Health Study II (PHS II) on the long-term risks and benefits of multivitamin use in male physicians [Sesso HD et al. JAMA2012].
PHS II was a randomized, double-blind, placebo-controlled, 2x2x2x2 factorial trial testing multivitamin, vitamin E, vitamin C, and beta-carotene. It was conducted by mail in 14,641 male physicians aged ≥50 years. A total of 7641 PHS I participants and 7000 new physicians were randomized to take an active multivitamin or its placebo, as well as for the other vitamin arms. For the multivitamin component, the primary cardiovascular (CV) endpoint was major CV events (nonfatal myocardial infarction [MI], nonfatal stroke, and CV death). The secondary endpoints were total and fatal MI, total and fatal stroke, ischemic and hemorrhagic stroke, CVD mortality, and total mortality. The participants were followed for a mean of 11.2 years, resulting in 164,000 person-years of follow-up.
Multivitamin compliance was 77% at 4 years, 72% at 8 years, and 67% at study end. Baseline characteristics were well balanced between the multivitamin and placebo groups. The cumulative incidence of major CV events at study end was not significantly different between the 2 groups (HR, 1.01; 95% CI, 0.91 to 1.10; crude log-rank p=0.69; Figure 1). Similarly, no significant differences were seen in the incidences of secondary endpoints (Table 1). There was a borderline significant reduction in MI death (27% vs 43%; HR, 0.61; 95% CI, 0.38 to 0.995; p= 0.048) that may have been due to chance, given its small case counts.
Figure 1. Major CV Events: Active Versus Placebo Multivitamins During 11.2 Years of Follow-Up.
Copyright © 2001 American Medical Association. All rights reserved.
Table 1. Association Between Randomized Multivitamin Assignment and Risk of Major CV Events and Mortality.
CV=cardiovascular; MI=myocardial infarction; aMean follow-up of 11.2 years for all 14,641 men through June 1, 2011; bAdjusted for age, Physicians' Health Study (PHS) cohort (original PHS I participant, new PHS II participant), randomized beta-carotene assignment, randomized vitamin E assignment, and randomoized vitamin C assignment and stratified on CV disease at baseline; cDefined as a composite endpoint consisting of the first of any of the following individual events: normal MI, nonfatal stroke, and CV death. The individual events do not sum to the total because each individual analysis assess the first event that occurs during follow-up. Therefore, a participant who for example has an MI and then dies of CV disease would be counted for both individual events but only once for the primary end point of major CV events; dIncludes both fatal and nonfatal events; eStroke type was unknown for 6 men in the active multivitamin group and for 16 men in the placebo group; fAdditionally stratified on baseline cancer. Copyright © 2001 American Medical Association. All rights reserved.
Notably, the total number of cancers—the other primary endpoint of the multivitamin component of the trial—was modestly but significantly reduced, with 1290 in the multivitamin group versus 1379 in the placebo group (HR, 0.92; 95% CI, 0.86 to 0.998; p=0.04). The total number of incident cancers among participants with a baseline history of cancer was also significantly lower in the multivitamin group (95) versus the placebo group (126; HR, 0.73; 95% CI, 0.56 to 0.96; p=0.02) but was not significantly lower among participants without a baseline history of cancer (1195 vs 1253; HR, 0.94; 95% CI, 0.87 to 1.02; p=0.15).
The results of the PHS II trial demonstrated no effect of long-term multivitamin use on CVD in men. The main reason to take a daily multivitamin is still for the prevention of vitamin and mineral deficiency, along with the potential reductions on total cancer. The investigators will provide additional results on the effects of multivitamins on the secondary endpoints of eye disease and cognitive function, and other important analyses of CV and cancer outcomes, along with extended follow-up of this trial cohort.
the United States alone, ~700,000 patients undergo multivessel coronary
revascularization yearly. Of these, 25% have diabetes [Smith SC et al. Circulation2002]. Valentin Fuster, MD, PhD, Mount Sinai School of Medicine, New York, New
York, USA, presented results from the Comparison of Two Treatments for
Multivessel Coronary Artery Disease in Individuals with Diabetes [FREEDOM]
According to Dr. Fuster, the FREEDOM trial was the largest prospective study of
revascularization strategy in patients with diabetes and multivessel coronary
artery disease (CAD) undergoing intensive medical treatment. Its purpose was to
compare mortality and major adverse cardiovascular events in diabetic
individuals with multivessel CAD randomized to either coronary artery bypass
graft (CABG) surgery or percutaneous coronary intervention (PCI). The primary
outcome measure was a composite of death from any cause, nonfatal myocardial
infarction (MI), and nonfatal stroke [Farkouh ME et al. N Engl J Med2012].
FREEDOM was sponsored by the National Heart, Lung, and Blood Institute, and
inclusion criteria were a diagnosis of diabetes as defined by the American
Diabetes Association guidelines: angiographically confirmed multivessel CAD
with severe (>70%) lesions in at least 2 major epicardial vessels, and an
indication for revascularization based on symptoms of angina and/or objective
evidence of myocardial ischemia. Prior to randomization, all qualifying angiograms
were reviewed by a study-related interventionalist and surgeon.
A total of 1900 patients with diabetes and multivessel CAD were enrolled from
2005 through 2010 from 140 international centers, and randomized to undergo
either PCI with drug-eluting stents or CABG. Patients were followed for a
minimum of 2 years (median among survivors, 3.8 years) and all patients were
recommended to be prescribed currently indicated antidiabetic,
antihypertensive, and lipid-lowering therapy by their treating physicians
[Farkouh ME et al. N Engl J Med 2012].
The mean patient age was 63 years, 29% were women, 83% had three-vessel
disease, and mean ejection fraction was 66%. As compared with PCI, the primary
outcome was significantly reduced with CABG at 5 years (18.7% vs 26.6%;
absolute difference, 7.9 percentage points; 95% CI, 3.3 to 12.5; p=0.005). The
benefit of CABG was driven by differences in rates of both MI (p<0.001) and
death from any cause (p=0.049). Stroke was more frequent in the CABG group,
with 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (p=0.03).
There was no statistical interaction between the benefit of CABG on the primary
endpoint and Synergy Between PCI with TAXUS and Cardiac Surgery (SYNTAX)
score or any other prespecified subgroup.
Dr. Fuster concluded that, in patients with diabetes and multivessel coronary
disease, CABG was of significant benefit compared with PCI and it is the
preferred method of revascularization in this setting. He noted that FREEDOM
was relatively short-term—7 years, with a minimum of 2 years and a median of
3.8—and long-term follow-up would provide a better understanding of the
comparative benefit of CABG, specifically on mortality.
Elizabeth A. Magnuson, MD, University of Missouri-Kansas City, Kansas City,
Missouri, USA, presented a cost-effectiveness analysis of the FREEDOM trial.
While CABG was associated with higher initial costs (~$9000) compared with PCI,
this cost difference was partially offset by lower costs associated with repeat
revascularization and, to a lesser extent, cardiac medications.
At 5 years, CABG improved quality-adjusted life expectancy by ~0.03 years while
increasing total costs by ~$3600 per patient. Over a lifetime, CABG was
associated with 0.66 quality-adjusted life year (QALY) gained and ~$5400 per
patient higher costs yielding an incremental cost-effectiveness ratio of $8132
per QALY gained.
According to Dr. Magnuson, results were robust under various sensitivity
analyses regarding the duration of the CABG effect on both survival and costs.
Results were also consistent across a wide range of subgroups. Based on these
findings, she concluded that CABG provides better long-term clinical outcomes
than drug-eluting stent PCI for patients with diabetes and multivessel CAD, and
these benefits are achieved at an overall cost that represents an attractive
use of societal healthcare resources. The outcomes also provide additional
support for existing guidelines that recommend CABG for diabetic patients with
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