Remote Ischemic Conditioning

Abstract

Although remote ischemic conditioning promises significant benefit to patients with a variety of acute and chronic illnesses, development of automated, clinically applicable devices has been slow. At least 3 small companies have launched efforts to develop useful tools intended for sale in European and North American markets. The market challenges and opportunities linked to the development of a cost-effective, reliable, and clinically effective device for the application of remote ischemic conditioning are presented in this article.

The clinical value of remote ischemic conditioning (RIC) must have been apparent more or less immediately after the discovery of the phenomenon by Przyklenk and colleagues in 1993. ¹ Since then, hundreds of studies have been conducted on RIC therapy for a variety of clinical conditions; most have shown promise and a few have proven clinical effectiveness. Yet a quarter century later, no universally accepted clinical indication for RIC exists, no device has attained US Food and Drug Administration (FDA) market approval, and the significant majority of medical practitioners are unaware of the potential of RIC therapy. ² In addition, those US clinicians who are familiar with RIC therapy may feel it has limited or no merit. Does RIC have a future in clinical medicine? From the perspective of a product developer, that question might be framed: Does a viable commercial market exist for this therapy?

Market Presence

Since RIC may be rendered with a standard blood pressure cuff, requiring only a person with very basic medical skills and an understanding of the treatment protocol, it’s possible to offer this treatment without any special investment. However, in practice, this approach is both impractical and costly, since it requires a dedicated individual to assure that a specific treatment algorithm of inflation/deflation cycles is applied over a treatment period of 40 minutes or more. An automated system would be much preferred, particularly for high-acuity populations such as patients with ST-segment elevation myocardial infarction (STEMI), who typically receive many treatments in several physical locations (ambulance, emergency department, and cardiac catheterization laboratory) over a very short time interval (in some cases, less than the 40 minutes required for RIC treatment). An automated device should be readily achieved, since the technical requirements of development and manufacturing are low compared with most new medical devices. Despite the simplicity of the concept, no large capitalization, established company has undertaken the development of a device for applying RIC, although several have shown interest in products developed by smaller start-up companies.

At least 3 start-ups have undertaken development of an automated RIC device. CellAegis Devices, Inc, a Canadian company, ³ was the first to commercialize an automated device for delivering RIC. The device, called autoRIC, received market approval in Europe in 2012 and in Canada in 2013 for the treatment of patients with STEMI undergoing primary percutaneous coronary intervention; this approval was obtained on the basis of small studies conducted with manual RIC that found this treatment reduced infarct size ⁴ and proprietary work demonstrating that autoRIC mimics manual therapy reliably. The device uses a straightforward approach: once activated, a controller unit inflates an air bladder limb tourniquet to 200 mm Hg, maintains this pressure for 5 minutes, deflates the bladder for 5 minutes, then repeats this cycle 3 more times. Currently, CellAegis is conducting clinical trials of RIC efficacy in ischemic heart disease and other conditions, mostly outside of the United States. ⁵

IC Therapeutics, Inc, a subsidiary of MEDITEX Capital LLC (a Texas-based health-care sector investment company incorporated in Delaware) is a US-based company with interest in invasive devices (for direct ischemic conditioning) and noninvasive devices (for RIC). ⁶ This company has a significant focus on RIC use in nonhospital setting; their core product (under development) is a “medical exercise bed” which offers limb occlusion RIC, blood flow counterpulsation, low oxygen content air (hypobaric oxygen therapy), heat, vibration, and neurostimulation. This combination is meant to mimic the physiologic consequences of strenuous exercise and is hoped to provide the benefits of exercise for those who are unable to exercise. Improved athletic performance may also be achieved for healthy individuals. IC Therapeutics has no marketed products or proprietary devices known to be under clinical study at this time, although the company remains active in clinician education about RIC.

LifeCuff Technologies, Inc (formerly Infarct Reduction Technologies, Inc) is a US-based company (incorporated in Delaware) ⁷ focused on the development of RIC devices that apply variable occlusive pressure, rather than a single set pressure, in fully integrated devices (Figure 1). The company holds several patents for software and hardware governing the application of occlusive (or subocclusive) arm or leg inflatable tourniquet pressure based on intermittent readings of extremity blood pressure from intelligence within the tourniquet. When applied over the length of several inches (ie, the width of a standard sphygmomanometer), the device creates extremity tissue ischemia reliably at the lowest pressure possible, which may have advantages with respect to reliability of extremity ischemia (since occlusion pressure for each cycle is determined by the patient’s actual blood pressure rather than an arbitrary pressure) and patient comfort. Their core technologies include treatment systems aimed at use in high-acuity conditions such as STEMI, military applications, and home use. LifeCuff Technologies has no marketed products and no publications on proprietary devices, but plans to launch clinical trials aimed at gaining product approval within the United States in the areas of wound healing, neurologic recovery after brain injury, and STEMI.

Figure 1.

The LifeCuff prototype. This device is designed as a fully integrated system. Once attached to a patient, a safety guard is removed (red tab) and the system is activated; thereafter, function is fully automatic. As a fully disposable system, no components require post-therapy management.

In addition to these commercial start-up companies, a device called DoctorMate has been developed by Beijing Institute of Renqiao Cardio-Cerebrovascular Disease Prevention and Control (Beijing, China), which is designed specifically for chronic application in the home. This device was used in a small clinical study to assess effects of twice daily, bilateral upper limb RIC treatment and recovery after stroke. ⁸ Finding that treatment was associated with greater functional recovery and fewer recurrent strokes compared with standard care, this device is now being studied in 3000 patients with stroke in China. Market intentions for this device are unclear.

All of these companies must convince health-care providers, payers, and the public that therapeutic RIC has value as an adjunct to standard care. Because RIC shows promise in many important medical applications, significant research efforts will be needed to define its value for each potential clinical indication.

Defining Market Value

Every therapeutic device must meet certain key conditions that define clinical value and which subsequently determine market value. At least 6 key questions must be addressed:

Does the device address a significant condition?

Very few ailments can be considered truly insignificant, but certainly interest is greatest for treatments of grave illness or injury. The fundamental characteristic of RIC is its potential to reduce patient harm, defined as preventing or limiting tissue damage from a disease state or injury; expediting tissue or organ recovery after insult; and/or reducing patient discomfort. Since regulators, clinicians, and patients uniformly seek these objectives, the appeal of RIC may be presumed for all but the most trivial medical conditions if proof of efficacy is established.

Does high-quality evidence of device efficacy exist?

To gain US FDA product approval, proof of meaningful clinical benefit (using clinical outcome end points) or evidence of highly probable clinical benefit (using accepted surrogate end points for clinical outcomes) must be provided. Approval on the basis of surrogate end points is, understandably, more difficult, but is possible for devices with a favorable safety profile. Despite abundant, high-quality basic science attesting to the physiologic effects of RIC, and significant advances in defining mechanisms of action, proof of clinical efficacy is scant for all clinical applications. For most conditions, published clinical work could be best described as promising.

The most compelling clinical evidence of treatment efficacy was offered by Botker and colleagues 7 years ago, who showed that manually applied RIC, delivered after onset of tissue injury but before restoration of perfusion, reduced the area of permanent injury following STEMI ⁴ ; this surrogate end point benefit was associated with improved clinical outcomes over 5 years. ⁹ Subsequent studies also found benefit with RIC using surrogate end points such as final infarct size, ST-segment resolution, creatinine kinase release, or left ventricular function ¹⁰ and suggested the therapy might have other benefits, such as lessening the impact of treatment delays for these highly time-sensitive patients. ¹¹ This line of study has been complicated by debate about the timing of RIC therapy relative to treatment for STEMI; although meta-analysis of blended data from perconditioning studies (RIC applied before and during reperfusion therapy) and postconditioning studies (RIC delivered after reperfusion therapy) show overall benefit, ¹² postconditioning may not provide equivalent benefits to perconditioning RIC. ¹³ Large randomized, controlled studies of automated RIC for perconditioning or postconditioning in patients with STEMI have not yet been completed.

Clinical investigation with RIC in patients undergoing cardiac surgery must be mentioned. Early work with RIC in cardiac surgical patients found benefit with surrogate end points, but 2 large-scale, randomized, placebo-controlled clinical trials of RIC during cardiac surgery published in 2015 showed no benefit in clinical outcomes or surrogate measures. ^14,15 Naturally, these negative studies raised important questions about the abilities of RIC. Post hoc analyses identified confounding influences (most importantly, the use of certain anesthetic drugs known to interfere with RIC mechanisms) that may have accounted for the disappointing results. ¹⁶

Despite setbacks, enthusiasm for RIC remains high among clinical investigators, and at the time of this writing, 245 clinical trials were registered with the US National Institutes of Health to test the effectiveness of RIC in treating ischemic heart disease, congenital and acquired structural heart disease, heart rhythm disorders, cardiac and other surgeries, kidney disease and injury, liver disorders, orthopedic injuries and treatments, stroke and other neurologic disorders, infections, gastrointestinal disorders, pain management, organ transplantation, trauma, burns, and others. ¹⁷

Is the product/therapy safe?

Although work to date has not been sufficient to confirm efficacy unequivocally, the safety signal with RIC is as good as it can be. No report of harm with RIC has been forthcoming from studies or clinical use. This is reasonable, since RIC treatment is effected through use of a tourniquet device that impairs blood flow into an arm or leg temporarily. Tourniquets have been used for ages (literally) without harm unless left in place for prolonged periods. By limiting the duration of constriction to 5 minutes or less, the chances of harm are extremely small. In broad application, theoretical risks exists, including harm in patients with unrecognized injuries of extremities, patients with blood disorders that increase the risk of in situ thrombosis, and those with bleeding disorders, for whom high pressure constriction could lead to dermal hematoma. Neuropathy is also a theoretical risk, although very unlikely with proper device design and application. Restricting blood flow into an extremity could result in derived harm, such as inability to administer intravenous medication into a limb under treatment. Many repeated ischemic conditioning treatments (the so-called hyperconditioning) have been linked to attenuation or loss of conditioning benefits, injury of collagen fibers, and changes in collagen production in animal studies that could have clinical implications. ¹⁸ Although not trivial, these risks seem small compared with benefits for serious medical conditions and are not expected to limit market acceptance or create regulatory impediments.

Is the cost of the device reasonable?

Hospital systems are under increasing pressure to reduce costs of delivering care. In the recently implemented Medicare Authorization and Children’s Health Insurance Program Reinstatement Act, US hospital systems will be rewarded for lowering costs of care and penalized if they do not. ¹⁹ Any new therapy seeking adoption in the United States should offer the potential to lower costs or improve care without increased costs. Similarly, in the United Kingdom, new medical devices must gain the approval of the National Institute for Health and Care Excellence program, a collaborative effort to develop cost-sensitive practice guidelines, before adoption by the National Health Service. ²⁰ Cost analyses must consider acquisition and utilization expenses for devices, and cost reductions made possible through device use. Manufacturers tend to focus on the expense side, since they can influence this variable through design and material choices. In the future, however, companies may be required to provide evidence of patient benefits that realize measurable care expense reductions.

For STEMI, the potential to reduce myocardial infarct size, with subsequent improved functional recovery, reduced hospital length of stay, and fewer expenses associated with care suggest a favorable cost: benefit relationship. Although high-quality, prospective financial analyses have not been done for RIC, an exploratory post hoc analysis of patients participating in a Danish trial of manual RIC (an expensive form of therapy) for STEMI found that RIC was cost-effective when the reduced need for additional care was considered. ²¹ Justifying costs for less expensive (and generally less well remunerated) activities such as postoperative pain management may be more complicated. Device pricing, then, may be influenced not only by costs of manufacturing and projected annual sales but also by potential benefit to specific customers.

As mentioned, only 1 automated RIC device has a presence in markets today. The autoRIC device consists of a reusable controller unit that remains in a charging bay until needed, and disposable components that wrap a patient’s extremity. The controller unit attaches to the disposable components and regulates operation of a compression bladder. After treatment, disposable components are discarded and the controller unit is cleaned and returned to a charging bay. Costs for controllers and charging bays are moderate and costs for disposable components are low. Handling, cleaning, and restocking expenses, as well as replacement costs for lost or worn controller units, must be considered in cost analyses for this and other systems with durable components.

Will the product be adopted into clinical practice?

Once safety and efficacy are established and costs are justified, physicians must be educated about new, disruptive products before they are likely to use them. Incorporating new products into care interferes with established behaviors. In the United States, the greatest challenge to be faced with the introduction of RIC devices may be teaching practitioners about RIC. Many practitioners are not familiar with the potential of the therapy, some have a negative impression of it, and others may consider such simple therapy just too good to be true. The impact of negative trials of RIC (such as the Effect of Remote Ischemic Conditioning on Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Graft Surgery [ERICCA] study and the Remote Ischemic Preconditioning for Heart Surgery [RIPHeart] study) will create resistance even if proof of efficacy is brought forth. Focused educational efforts are costly and will challenge start-up companies attempting to launch independently.

Do patients accept the therapy?

In the acute care setting, patient acceptance will come readily when therapy is recommended by a health-care provider. Outside of the acute care setting, patient acceptance is less certain. IC Therapeutics is focused on chronic outpatient therapy, while CellAegis Devices and LifeCuff Technologies envision RIC devices suitable for home or office use to treat chronic illnesses. Recent reports from Asia ⁸ and the United Kingdom ²² suggest the possibility of benefit with both acute and chronic RIC therapy after stroke. In the Chinese study, highly meaningful functional recovery benefits were reported when RIC was applied to 2 limbs, twice each day, for up to 300 days. ⁷ Patient acceptance for such intrusive treatment will be more challenging but may be achieved on the basis of compelling evidence of benefit for a devastating condition. Similarly, cancer is a leading cause of death and disability. Studies of chronic RIC effects on organ function among cancer patients receiving treatments are registered with the US National Institutes of Health ¹⁷ ; improved quality of life for patients with cancer may drive treatment acceptance.

Areas of Opportunity

Although RIC is under study for many clinical conditions, cardiovascular care is most notable from a corporate perspective because of the body of work done to date, the potential for demonstrating benefit (using surrogate and clinical end points), the high-acuity setting, and the prevalence of disease. Also, the development pipeline for new stroke and STEMI medications is small; during the annual Scientific Sessions of the American Heart Association in November, 2016, then FDA Commissioner Robert Califf, MD, noted “Cardiovascular medicine is not a place where industry is investing right now in new molecules.” ²³ The paucity of new, effective medications creates opportunity for effective devices.

In addition to the usual commercial medical applications, other applications may be viable market opportunities. Remote ischemic conditioning may enhance athletic performance ²⁴ although results have been variable, perhaps indicating that responder and nonresponder populations exist. ²⁵ Remote ischemic conditioning also shows promise in attenuating traumatic brain injury. ²⁶ If confirmed, RIC may have successful application on fields of combat and sport, where concerns have been raised over the long-term consequences of even mild to moderate head trauma with associated concussion. Remote ischemic conditioning lessens pain after surgeries, ²⁷ RIC cardiovascular effects appear to have an interaction with opioid medication use, ²⁸ and the opioid receptor/Akt pathway is involved in at least some RIC signaling. ²⁹ Further work into RIC effects on opioid signaling pathways and pain perception may yield important opportunities for chronic pain management and addiction recovery.

The Path Forward

Barriers to commercialization of RIC in the US marketplace include definition of suitable target populations or conditions, the need for definitive evidence of meaningful benefit, demonstration of safety, appropriate pricing, physician adoption, and patient acceptance. The greatest barriers can only be overcome with substantial resource investment in clinical research. In a capital market, research investment requires assurances of success and profits. In this regard, RIC has liabilities:

The mechanisms of RIC are not understood well

Investors and grantors want to understand how a proposed therapy works. Uncertainty about the fundamental RIC mechanisms of action has caused some investors to shy away. Recent advances are of considerable help in generating interest among investor groups, but until a clearer understanding exists, investors may question whether the science is sound.

Remote ischemic conditioning is not glamorous

Investors like impact nearly as much as returns. Investing in a start-up company that might deliver an implantable artificial eye and restore sight to the blind will be more alluring than investing in an automatic blood pressure cuff. The derivative benefits of RIC to patients may be large but not as dramatic as some other technologies competing for investment dollars.

Remote ischemic conditioning is not new

After more than 2 decades, RIC can no longer claim to be a new concept. Speculative investors tend to consider older concepts as more likely to fail, since high potential concepts are funded readily and proven (or disproven) quickly.

Remote ischemic conditioning doesn’t yet have a primary target population

As a complex biological mechanism that preserves and restores injured tissue, RIC study has triggered many lines of study. This has resulted in some degree of clinical research diffusion, with lots of small studies and few large studies, and arguably no definitive studies for any single indication.

Remote ischemic conditioning has had some black eyes

Negative studies can be hard to overcome, even when important faults are recognized in their design. Since the publication of the ERICCA and RIPHeart cardiac surgical studies, investors have been more reluctant to discuss RIC.

Given these facts, the path to introduction of RIC into the US market will be challenging. The key to successful market release is investment and funding for clinical research focused on a few, high-yield medical indications. Without it, definitive proof of efficacy will not be generated. Cardiologists (particularly interventional cardiologists) tend to be early adopters of new technologies. If ongoing studies provide robust evidence of merit for a cardiac indication, physician awareness will increase quickly as information is presented at medical conferences. As long as product pricing is set to assure hospitals try the RIC device, physicians will likely embrace it. New payment models that hold hospital systems accountable for the welfare of patients for 30, 60, or 90 days after hospitalization will encourage interest in products that offer improved outcomes acutely and after hospital release. Compelling evidence of benefit could lead to recommendations for RIC in clinical practice guideline statements. Investment into additional clinical trial work, some of which must be based in the United States, may lead to expanded uses of RIC including home use for chronic conditions. Investment into basic research will continue to be essential, since clarification of mechanisms of action may lead to new insights into how to best render RIC.

Summary

After 25 years, the promise of RIC as an adjunct to clinical medicine has not yet been realized. Three North American start-up companies have been launched in pursuit of a marketable automated RIC device, using different technical solutions, and 1 has been approved for clinical use outside of the United States. Significant challenges exist for an automated RIC device to find success in the US marketplace, but these may be overcome with sufficient investment in support of clinical investigation and device perfection. Much is dependent on the outcomes of ongoing clinical trials and the willingness of investors and granting agencies to continue research funding. The potential for meaningful clinical benefit in a variety of clinical settings appears high, and the opportunity to realize a profitable product with far less investment than would be required for a new drug or complex device should attract speculative investment and expedite commercialization.