ACCEL
American College of Cardiology Extended Learning

Genetic Testing for HCM: What Do We Learn?
And do genotype-negative patients have HCM?

There is the concept of big data, in which important knowledge can be gleaned from an analysis of the clinical experience of millions of patients. Then there is the explosion of molecular data in which one report by Ashley et al. presented the results of a single patient based on an analysis of 2.6 million single nucleotide polymorphisms.1 This suggests large—even humongous—untapped opportunities to use data to improve health outcomes

A few years ago, the National Research Council proposed a new data network to integrate emerging research on the molecular makeup of diseases with clinical data on individual patients.2 Success here could drive the development of a more accurate classification of disease and ultimately enhance diagnosis and treatment.

“Currently, a disconnect exists between the wealth of scientific advances in research and the incorporation of this information into the clinic,” said Susan Desmond-Hellmann, MD, MPH, co-chair of the committee that authored the report and Chancellor of the University of California, San Francisco, CA. “Often it can take years for biomedical research information to trickle to doctors and patients, and in the meantime wasteful health care expenditures are carried out for treatments that are only effective in specific subgroups.”

In his 2015 State of the Union Address, U.S. President Barack Obama announced the Precision Medicine Initiative, a research effort to revolutionize how we improve health and treat disease. Launched with a $215 million investment, the concept of “precision medicine” (an evolution to what has been called personalized medicine) was used in that National Research Council monograph mentioned above,1 in which the authors explain that their use of “precision” was intended to avoid the implication that medications would be synthesized personally for single patients. Rather, they hoped to convey a broader concept that would include precisely tailoring therapies to subcategories of disease, often defined by genomics.

Biobanking and Data Sharing

Precision medicine will require a large cohort of individuals willing to share their electronic medical and genomic data. Recently, Euan A. Ashley, MD, FACC, of the Departments of Medicine and Genetics in California’s Stanford University, noted that the first generation of genomic data will mostly come from genotyping chips containing 1 million to 2 million previously identified genetic variants or enhanced exome sequencing, which targets the sequence of the approximately 20,000 genes.3

Some countries, such as the United Kingdom and Denmark, already have large-scale biobanks. In the United States, Dr. Ashley noted that the Million Veteran Program reports recruitment currently at more than 300,000 individuals, with thousands having been sequenced and hundreds of thousands having been genotyped. Other U.S.-based cohorts include the eMERGE consortium (funded by the National Human Genome Research Institute), which combines electronic medical record data and genomic data from almost 200,000 individuals.

Although challenges remain, results published by Dr. Ashley and colleagues suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.1

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is an inherited disease of the heart muscle and among the most common Mendelian cardiac diseases, occurring in one in 500 people. Advances in genetics have facilitated identification of a subpopulation of patients with pathogenic variants in cardiac sarcomere genes. As Dr. Ashley noted recently in the Journal of the American College of Cardiology (along with Matthew T. Wheeler, MD, PhD) coding regions of numerous cardiac sarcomere genes are routinely sequenced in clinics today.4 Excluding those patients with discrete upper septal thickening, clearly pathogenic variants are identified in 30% to 50% of patients, thus marking a subset of “sarcomeric” HCM.

Genetic testing can tell a lot, according to Dr. Ashley, ranging from important information regarding optimal management strategies to risk and response to drugs. As he and colleagues reported in JACC,5 for example, there are distinctive clinical and biophysical features that characterize HCM associated with thin-filament mutations that differ from the more common thick-filament disease. Thin-filament HCM is associated with less prominent and atypically distributed LV hypertrophy, increased LV fibrosis, higher likelihood of adverse LV remodeling leading to functional deterioration, and more frequent occurrence of triphasic LV filling, reflecting profound diastolic dysfunction.

So do genotype negative patients have HCM? As Dr. Ashley explained, some patients may suffer from “HCM of the elderly.” Such patients were once referred to as having discrete upper septal hypertrophy. Today, a more accurate way of expressing that is discrete upper septal thickening where there is a sigmoid septum but LV mass and papillary muscles are often normal; gradients can be high and ventriculo-vascular stiffness is common, but family history is rare. What is this? A non-sarcomeric form of HCM? It’s sarcomeric, but the protein is unknown? Is it just hypertension or some complex genetic disease? Is it multifactorial disease or just a variation of normal? There is no simple answer, said Dr. Ashley. It is certainly associated with age but, when seen in isolation, it does not appear to have any effect on mortality. “There is no perfect answer,” he said, “but we all deal with this uncertainty.”

Another group of genotype-negative patients are represented by a 17-year-old male who presented in his early teens with a significant family history, and family screening revealed even more cases than previously known. The patient had a moderate gradient, high LV mass, a lot of delayed-gadolinium enhancement, and ventricular tachycardia.

At AHA.14, Dr. Ashley reported unpublished data from the Stanford Cardiome Study: they have found 64 HCM patients who are genotype negative. “These are the patients we scratch our heads over the most,” he said. “We see patients who appear to have classic hypertrophic cardiomyopathy: reverse curvature and asymmetry, but negative sarcomere sequencing—as we currently do sarcomere sequencing today.”

It may be a coding variant in a gene of the cardiac sarcomere that is not on the sequencing panel. Maybe it’s a regulatory variant in a sarcomere gene or a variant in a non-sarcomere gene, such as a signaling gene. We know a number of signaling pathways that cause hypertrophy. Could some of them cause an asymmetric hypertrophy? Or maybe there is epigenetic modification of a sarcomere gene. At least we are probably confused at a higher level than was possible just a few years ago.

He added, “We offer genetic testing to all our HCM patients at Stanford and spend a significant amount of time on family history and thinking about the whole family as our patient.” There is no clear answer, he admits, to the question of whether genotype-negative patients have HCM. “I am not sure I have answered that question for you.” Some do, he said, and some don’t; there is probably a useful debate to be had around the issue of semantics.

Overall, Dr. Ashley said that development of methods integrating genetic and clinical data will assist clinical decision-making and represents a large step towards individualized medicine. The transition to a new era of genome-informed medical care will need a team approach, he added, incorporating medical and genetics professionals, ethicists, and health care delivery organizations.

References:

  1. Ashley EA, Butte AJ, Wheeler MT, et al. Lancet. 2010;375:1525-35.
  2. Committee on a Framework for Development of a New Taxonomy of Disease, National Research Council. Washington, DC; National Academies Press; 2011.
  3. Ashley EA. JAMA. 2015;313:2119-20.
  4. Wheeler MT, Ashley EA. J Am Coll Cardiol. 2015;65:570-2.
  5. Coppini R, Ho CY, Ashley E, et al. J Am Coll Cardiol. 2014;64:2589-2600.

Physical Activity as Vital Sign
The exercise prescription to prevent CAD

We have physical activity recommendations from the Centers for Disease Control and Prevention,1 the American College of Sports Medicine,2 the U.S. Surgeon General,3 the American Heart Association,4 and the ACC.5 All of the publications affirm the primary role of exercise in preventing chronic disease and in maintaining health throughout life. Several principles emerge from these documents, including:

  • any exercise is better than none,
  • more exercise is better than less,
  • different types of exercise (aerobic versus resistance) yield distinct favorable outcomes,
  • and activity recommendations should be enabling and flexible, and avoid setting up barriers.

In terms of the mode of exercise, there is aerobic, resistance, flexibility, and balance exercises as well as specific types of activities, such as walking and biking. Frequency is determined by the number of active sessions per day or per week and often qualified as being the number of sessions (bouts) of exercise/activity ≥ 10 min in duration/length

Intensity is determined by the rate of energy expenditure (TABLE). Walking at 3.0 miles per hour requires 3.3 metabolic equivalents (METs) of energy expenditure and is therefore considered a moderate-intensity activity that noticeably accelerates heart rate (HR). Vigorous-intensity activities are those that require a large amount of effort and causes rapid breathing and a substantial increase in HR. Adherence may be better with moderate activities, especially among sedentary individuals.

You may know what METs stands for without specifically understanding what it means. One MET is defined as the energy cost of sitting quietly and is equivalent to a caloric consumption of 1 kcal/kg/hr. Instead of sitting quietly, a person’s caloric consumption is three to six times higher when being moderately active (3-6 METs) and more than six times higher when being vigorously active (> 6 METs). (Some recommendations include 6 METs in the “moderate” category while others consider it the starting point of vigorous activity.)

How does physical activity prevent CHD? Vera Bittner, MD, FACC, is a professor of medicine and Section Head of Preventive Cardiology at the University of Alabama, Birmingham; she was a co-author of the AHA scientific statement.4 To answer the question, Dr. Bittner points to the Women’s Health Study, which included self-reported physical activity.6 Based on increasing levels of activity levels, there was a strong dose-dependent reduction in CHD (up to 52%) and CVD (up to 41%). Changes in risk factors (e.g., hypertension, lipids, BMI, even blood glucose levels) explained 35.5% of the CHD reduction seen across almost 11 years of follow-up as well as 59.0% of the CVD reduction seen.

On average, according to the recent ACC/AHA lifestyle guidelines,5 aerobic activity compared with control interventions, is associated with:

  1. reduction in low-density lipoprotein cholesterol (LDL) of 3 to 6 mg/dL,
  2. reduction in non-high-density lipoprotein cholesterol (HDL) of 6 mg/dL,
  3. no consistent effect on triglycerides or HDL, and
  4. a reduction in both systolic (-2 to -5 mm Hg) and diastolic (-1 to -4 mm Hg) BP.

Again, compared with control interventions, adults undertaking regular resistance training experience reductions (on average) in LDL, triglycerides, and non-HDL cholesterol of 6 to 9 mg/dL.

An Exercise Prescription

What are the attributes of an “ideal” exercise prescription to prevent CAD? Dr. Bittner suggests a universal yet individualized approach, based on physiologic age, “athletic” ability/fitness, comorbidities, and (of course) patient preferences. Also for consideration: feasibility, whether that relates to time, equipment, or environment. (Don’t recommend a health club membership to someone who lives an hour away from the nearest such facility.)

In brief, any activity is better than no activity and more activity provides incremental benefits. Also, when considering an exercise prescription, consider one that is sustainable and safe. Yes, MI risk is increased during vigorous activity, especially among those not habitually active. However, Dr. Bittner emphasizes that for inactive people who gradually progress to moderate-intensity activity, there is no known increased risk of sudden cardiac events. There is also a very low risk of musculoskeletal injuries.

According to the 2008 physical activity guidelines,1 habitually active persons can gradually increase to vigorous intensity without consulting a health care provider. Conversely, people who develop new symptoms when increasing their levels of activity should consult a health care provider. Plus, people with symptoms or known chronic conditions should be under the regular care of a health care provider.

For an effective level of physical activity, Dr. Bittner said, there are substantial health benefits associated with moderate aerobic activity ≥ 150 min (2.5 hrs) a week or vigorous physical activity ≥ 75 min/week or an equivalent combination of moderate and vigorous aerobic activity. Bouts of activity of ≥ 10 minutes are effective when spread throughout the week. Additional health benefits are associated with muscle-strengthening activities of moderate-to-high intensity when they involve all major muscle groups and are performed 2 or more days a week.

In short, she added, physical activity should be a vital sign assessed at every visit.

References:

  1. [No authors listed.] Physical Activity Guidelines Advisory Committee. Physical Activity Guidelines Advisory Committee Report, 2008. Washington, DC: U.S. Department of Health and Human Services; 2008. health.gov/paguidelines/report. Accessed July 31,2015.
  2. Nelson ME, Rejeski WJ, Blair SN, et al. Circulation. 2007;116:1094-105.
  3. [No authors listed.] Office of the Surgeon General (U.S.). The Surgeon General’s Vision for a Healthy and Fit Nation. Rockville, MD: 2010. ncbi.nlm.nih.gov/books/NBK44660. Accessed July 31,2015.
  4. Fletcher GF, Ades PA, Kligfield P, et al. Circulation. 2013;128:873-934.
  5. Eckel RH, Jakicic JM, Ard JD, et al.. J Am Coll Cardiol. 2014;63:2960-84.
  6. Mora S, Cook N, Buring JE, et al. Circulation. 2007;116:2110-8.

Slipping into Reverse
New agents under study for reversing target-specific oral anticoagulants

The direct thrombin inhibitor dabigatran as well as the anti-factor Xa (fXa) agents rivaroxaban, apixaban, and edoxaban (listed in order of U.S. approval for stroke prevention in nonvalvular atrial fibrillation [AF] patients), are a new generation of oral anticoagulants that are transforming clinical practice. While these target-specific oral anticoagulants (TSOAs) overcome some of the difficulties associated with anticoagulation with vitamin K antagonists, one reason for a slower than-expected uptake in clinical practice may be the absence of specific reversal agents.

Serious bleeding events are low and the need for reversal of any anticoagulant is relatively rare: over a 12-month period ending in June 2013, there were about 6.8 million patients taking anticoagulants in the United States, of whom approximately 345,000 (5.1%) presented to the emergency room with a bleeding event.1 Approximately 228,000 of those patients warranted hospital admission.

Also, the rapid offset of the TSOAs (half-life of rivaroxaban is 4 to 9 hours and 12 to 17 hours for dabigatran and apixaban) obviates the need for reversal in most situations, although antidotes for these agents would be beneficial to manage patients who require urgent surgery or interventions and to treat individuals with life-threatening bleeds.

In the summer of 2015, Mark Crowther, FRCP, MD, FACC, a professor of medicine at McMaster University, Canada, published a review of the anticoagulants, their current use, and future potential.2 Unlike the anti-fXa agents, the absorption of dabigatran can be reduced by activated charcoal if administered shortly after ingestion and it can be removed from the blood with hemodialysis.

Prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VIIa all show some activity in reversing the anticoagulant effect of these drugs but this is largely based on ex vivo, animal, and volunteer studies. It is unclear, which, if any, of these approaches is the most suitable for emergency reversal.

Three novel molecules (idarucizumab, andexanet, and PER977) may provide the most effective and safest way of reversal. These agents are currently in premarketing studies.

Universal Antidote for Factor Xa Inhibitors

Recently, Dr. Crowther presented the results of a phase III clinical trial of Andexanet alfa (PRT064445), a universal antidote for fXa inhibitors. An FDA-designated breakthrough therapy, this protein acts as a decoy for direct fXa inhibitors, binding to anti-fXa agents in a dose-dependent manner, preventing them from acting on the coagulation cascade. The new agent is being studied with all of the direct fXa inhibitors: apixaban, rivaroxaban, and edoxaban. It is also being studied as an antidote for patients on enoxaparin, a low-molecular-weight heparin (LMWH) and indirect fXa inhibitor. The drug does not seem to be effective against the factor IIa inhibitor dabigatran.

The trial is known as ANNEXA (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors) with ANNEXA–A referring to the specific apixaban study (presented at AHA.14) and ANNEXA–R referring to the rivaroxaban study (data presented at ACC.15).

In ANNEXA–A, 33 healthy volunteers were given apixaban 5 mg twice daily for 4 days and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg intravenous (IV) bolus (n = 24) or to placebo (n = 9). The new agent was well-tolerated and met all pre-specified primary and secondary efficacy endpoints with p < 0.0001. Fully 100% of andexanet-treated participants had ≥ 90% reversal of anti-fXa activity and restoration of thrombin generation to baseline (pre-anticoagulant) levels. Andexanet produced near complete normalization of all coagulation parameters measured within 2 minutes of infusion completion and the effect lasted 1-2 hours with bolus dose.

A second part of ANNEXA was presented at the June 2015 International Society on Thrombosis and Haemostasis Congress in Toronto, Canada. This analysis included 31 healthy volunteers also given apixaban 5 mg twice daily for 4 days and both the original 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n = 23) or to placebo (n = 8). The agent has a very short half-life, so in order to get continuing effect, it needs to be delivered as a continuous infusion. Andexanet acts as a ‘decoy,’ so the fXa inhibitor binds to the decoy and is unable to maintain an anticoagulant effect as it is removed from the body. Again, the second part of ANNEXA–A study achieved all primary and pre-specified secondary endpoints with high statistical significance.

Specifically, the anticoagulant activity of apixaban, as measured by anti-factor Xa activity, was reversed by 93.5% (p < 0.0001 versus placebo). Following completion of the 2-hour continuous infusion of andexanet alfa, the anticoagulant activity of apixaban remained significantly reversed, by 92.7% (p < 0.0001). These two endpoints demonstrate that andexanet alfa produced rapid reversal of the anticoagulant effect of apixaban, which was sustained for the duration of the infusion. Andexanet alfa significantly reduced the level of free unbound apixaban in the plasma and restored thrombin generation to normal. The new agent was well tolerated, with no serious adverse events, thrombotic events, or antibodies to Factor X or Xa reported.

It should be noted that data have not been reported yet evaluating these agents in the setting of active bleeding. Dr. Crowther explains that in the case of an individual with an upper gastrointestinal bleed due to an ulcer, from what is known now a single bolus of andexanet alfa might be sufficient, which would provide a 30- to 60-minute window to allow an interventionalist to perform a procedure without any anticoagulant effect. On the other hand, in the event of a patient requiring a longer surgical procedure, then it likely would be necessary to utilize prolonged infusion rather than a single bolus of andexanet.

What about the rivaroxaban study? In the first part of ANNEXA–R, 41 healthy volunteers were given rivaroxaban 20 mg once daily for 4 days to steady state. They were then randomized in a 2:1 ratio to receive either andexanet administered as an 800 mg IV bolus (n = 27) or placebo (n = 14).

For the primary endpoint, andexanet alfa reduced the anti-fXa activity of rivaroxaban from baseline to nadir by >90%, a highly significant difference (p < 0.0001). For the secondary endpoints:

  • Significantly more andexanet alfa subjects (26 of 27) than placebo subjects (0) had a 90% or greater reduction in anti-Factor Xa activity from baseline to nadir (p < 0.0001).
  • The free (unbound) rivaroxaban concentration from baseline to nadir was reduced significantly by andexanet compared with placebo
  • (p < 0.0001).
  • Endogenous thrombin potential significantly increased from baseline to peak in andexanet subjects compared with the placebo volunteers
  • (p < 0.0001).
  • Finally, 26 of 27 andexanet alfa subjects returned to the normal range of thrombin generation within 10 minutes of the end of the bolus administration.

The second part of the ANNEXA-R study is expected to be presented soon in these healthy volunteers who, after receiving an 800 mg IV bolus, received a continuous infusion of 8 mg/min for 120 minutes or placebo.

Idarucizumab for Dabigatran Reversal

Also in June of 2015, investigators published an interim analysis of a prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in 90 patients who had serious bleeding (group A) or required an urgent procedure (group B).3

Idarucizumab is a humanized MoAb fragment with high affinity for the oral direct thrombin inhibitor dabigatran that selectively and immediately neutralizes its anticoagulant activity.4 The data indicate that the antidote effectively and within minutes of administration neutralized the activity of dabigatran with a satisfactory safety profile. Normal hemostasis was reported in more than 90% of the patients who underwent procedures after the administration of idarucizumab. Concentrations of unbound dabigatran remained below 20 ng/ml at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in two patients and one patient, respectively.

In an accompanying editorial, Kenneth A. Bauer, MD, chief of the hematology section, VA Boston Health Care System, and director, Thrombosis Clinical Research, Beth Israel Deaconess Medical Center in Boston, MA, noted that, without a control group, it is difficult to assess the clinical benefit of idarucizumab in patients with dabigatran-related bleeding.5 The mortality in the study population was high at 20%; half the deaths occurred more than 96 hours after the administration of the antidote and were attributable to coexisting illness.

Dr. Bauer wrote, “Given that the half-life of dabigatran is 12 to 14 hours if renal function is normal, how important is it to be able to neutralize the anticoagulant activity of dabigatran rapidly in addition to providing supportive care measures? [The] location and size of the lesion along with the coexisting conditions of the patient may have a greater effect on prognosis than the ability to rapidly neutralize an anticoagulant that the patient is taking.”

Finally, perosphere or PER977 is a small, synthetic, water-soluble, cationic molecule that is a nonspecific reversal agent which binds to several of the direct oral anticoagulants by means of electrostatic interactions. In vitro and in vivo studies indicate that PER977 reverses anticoagulation with each of the new oral agents mentioned above. This reversal effect is due to direct binding to the anticoagulant molecule but no binding to blood coagulation factors or to other proteins in the blood.

On April 2, 2015, the FDA granted Fast Track designation for PER977 and phase III trials are in the final planning stages.

References:

  1. Truven Marketscan® Commercial, Medicare Supplemental, and Medicaid Databases. Time period: January 1, 2012, to June 30, 2013. Extracted April 2014. Unpublished results.
  2. Crowther M, Crowther MA. Arterioscler Thromb Vasc Biol. 2015 Jun 18. [Epub ahead of print]
  3. Pollack CV Jr, Reilly PA, Eikelboom J, et al. N Engl J Med. 2015 Jun 22 [Epub ahead of print]
  4. Glund S, Stangier J, Schmohl M, et al. Lancet. 2015 Jun 15. [Epub ahead of print]

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Novel Agents

Keywords: CardioSource WorldNews, American Heart Association, Anticoagulants, Antithrombins, Atrial Fibrillation, Benzimidazoles, Centers for Disease Control and Prevention (U.S.), Chronic Disease, Morpholines, Polymorphism, Single Nucleotide, Pyrazoles, Pyridines, Pyridones, Sports Medicine, Stroke, Surgeons, Thiazoles, Thiophenes, Vitamin K, beta-Alanine


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