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Summary

  • The target market for NYHA Class IV heart failure (HF) in the US and EU is around 250,000 patients and is strongly contested by Thoratec (THOR) and HeartWare (HTWR).
  • NYHA Class III heart failure, with ~5 million patients in the US and EU, is a much larger and hugely coveted prize with a tiny percentage share worth $billions.
  • Sunshine Heart (SSH) C-Pulse is the only long-term mechanical circulatory support (MCS) device to successfully complete a pilot trial showing safety and efficacy in Class III HF patients.
  • The Thoratec HeartMate II Revive-It trial and the Sunshine Heart C-Pulse Pivotal trial are the only current FDA approved trials of MCS devices for NYHA Class III Heart Failure.
  • The C-Pulse trial, being a Pivotal trial leading to PMA application, is a quantum leap ahead of the HeartMate II Pilot trial which requires a subsequent Pivotal trial.

This article follows on from an earlier article, "Sunshine Heart: The 2 Horse Race For First In The NYHA Class III HF Stakes," and further addresses reasons for delayed starts to both the Revive-IT trial using Thoratec's HeartMate II Left Ventricular Assist Device (LVAD), and the Counter HF trial using Sunshine Heart's C-Pulse heart assist device.

But the main thrust of this article is about -

  • Matters of patient selection criteria, particularly in relation to inappropriate inotrope use in heart failure (HF) patients and the effect of this on enrollments; and
  • Why inotrope therapy criteria might prevent or severely limit any patient enrollments for the Revive-IT trial, thus turning this into a one-horse race for Sunshine Heart C-Pulse system.

For readers unfamiliar with heart failure and its treatment, and those wishing to refresh their understanding, it is both desirable and necessary to provide some background information about:

  • Thoratec's HeartMate II left ventricular assist device (LVAD);
  • Sunshine Heart's C-Pulse counter-pulsation system;
  • What heart failure is and its progressive nature;
  • What happens when optimal drug therapy (OMT) is insufficient;
  • The case for earlier intervention in HF with mechanical circulatory support (MCS) devices;
  • The role of inotropes in treating acute decompensated heart Failure; and
  • The penalty regime encouraging inappropriate provision of inotrope infusion therapy

This information under the above headings is provided as Supplemental Information at the end of the main article.

For readers familiar with the above please feel free to go straight to the main discussion below which encompasses:

  • Understanding the lengthy delays in getting to the starting gate
  • When did the trials actually reach the starting gate and become "Enrollment Ready"?
  • Patient selection
  • Patient selection, in itself, should not alter the outcome of the trials
  • Initial patient selection could have an enormous effect on subsequent trial enrollment rates
  • The importance of "Responders" early in the trials to accelerate completion of the trials
  • Why inappropriate inotrope infusion therapy is creating confusion in applying selection criteria in the patient enrollment process
  • Implications of determining actual degree of Inotrope dependence for the Counter HF C-Pulse trial
  • Implications of determining degree of Inotrope dependence for the Revive-IT HeartMate II trial
  • Conclusions

Understanding the lengthy delays in getting to the starting gate

For both the Thoratec (NASDAQ:THOR) HeartMate II Revive-It Pilot trial and the Sunshine Heart (NASDAQ:SSH) C-Pulse Counter HF Pivotal trial there were extensive delays between the dates each of the studies were first approved and readiness to accept enrollments.

Revive-It trial delays (Thoratec's HeartMate II)-

Detailed reasons for these delays for the Revive-It trial, including change from HVAD to HeartMate II and blood clotting issues, were given in Part I of this article series, "Sunshine Heart: The 2 Horse Race For First In The NYHA Class III HF Stakes" (see link above).

Counter HF trial delays (Sunshine Heart's C-Pulse)-

Similarly, there were delays for the Counter HF trial between first approval by the FDA and when the trial was enrollment ready. Counter HF had none of the dramas of the Revive-It trial as detailed in Part I. But recruitment and activation of trial sites is a lengthy process, and Sunshine Heart also undertook multiple device modifications that required FDA approval. FDA approval was not received until 3rd quarter 2013. These modifications included improving the electrical signal between the heart and the device, and a 5 inch extension to the PIL external lead to assist in reducing exit site infections. Exit site infections occurred in a number of patients in the Feasibility trial. There have been nil exit site infections in the 8 patients implanted in the EU and the modified device is showing even better clinical results than for the Feasibility trial. One EU patient has already been able to be weaned off the device and another declared the improvement in his condition as a "miracle".

Also in this period, Sunshine Heart developed a fully implantable version of the C-Pulse system and successfully carried out acute and chronic animal trials.

The time interval was well spent despite the delay in starting enrollments.

When did the trials actually reach the starting gate and become "Enrollment Ready"?

Revive-It Thoratec HeartMate II trial assumed "Enrollment Ready" date-

Revive-It trial was enrollment ready by August 2013, some 7 months after the replacement of HVAD with HeartMate II and before the trial was voluntarily suspended in December 2013 for blood clotting concerns. Resumption of the trial was approved by the FDA on 12 March 2014 (see here).

So let us assume April 2014 as the effective "Enrollment Ready" date for the Revive-It trial using HeartMate II.

Counter HF Sunshine Heart C-Pulse trial assumed "Enrollment Ready" date-

The FDA approved the modifications to the device for use in the trial around the end of September 2013. Eight of the targeted 35 trial sites were activated by that time. So let us assume October 2013 as the effective "Enrollment Ready" date for the Counter HF trial using the C-Pulse as modified for the trial.

The table from Part I can then be updated as follows -

Looking at the revised table above it can be seen that the bigger issue has been getting to the point of being ready to accept patients for enrollment.

Actual enrollment numbers are still disappointing, though in my opinion, not entirely unexpected for reasons elaborated on below.

Patient selection -

I, for one, am not overly concerned by the slow start to enrollments in the C-Pulse trial. I would be fairly certain it is more to do with a great deal of care and time in educating site personnel on interpreting and applying the enrollment criteria to prospective enrollees than anything else. Practical difficulties faced in applying the criteria in relation to inotrope usage, and the importance of ensuring appropriate patients are enrolled for C-Pulse implants, particularly in the initial phase, are discussed below.

Both the Counter HF and the Revive-It trials are randomized (1:1 basis) comparator trials of these devices versus best medical therapy.

Patient selection, in itself, should not alter the outcome of the trials

If the devices are in fact measurably more effective than optimal medical therapy for patients that meet the selection criteria, then patient selection should not materially alter the outcome of the trial.

If slightly sicker patients are selected, both the device group and the control group might have lesser outcomes than for a slightly healthier patient set. But there should still be a superior outcome for the device group versus the control group.

For example, a 30 day re-hospitalization rate of 10% for the device group and 35% for the control group in a slightly sicker overall population of patients would be similarly meaningful as 5% and 35% respectively in a slightly healthier overall patient population.

Initial patient selection could have an enormous effect on subsequent trial enrollment rates

For the initial implant/s at each individual site, patient selection assumes enormous importance for the success of the trial.

For the C-Pulse Feasibility trial, 60% of patients were "responders" showing an improvement in NYHA HF classification. Of the remaining 40%, one died of a non-device related infection and the remainder showed no worsening of HF. This is a positive outcome for the C-Pulse therapy because a degree of worsening would be expected for HF patients receiving the alternative of optimal medical therapy. For an excellent presentation on the Feasibility study results and on heart failure visit Sunshine Heart website media page and listen to William T Abraham MD.

Based on the C-Pulse Feasibility trial results, 40% of initial Counter HF patients implanted by any site could in fact not show a measurable response and in fact there could be a run of patients not showing a measurable response.

This could diminish enthusiasm for further implants even though these patients might well be performing far better than the control group if compared, for instance, on the basis of re-hospitalization rates for worsening heart failure. Despite 40% of patients not improving by at least one NYHA Class in the Feasibility trial, re-hospitalization rates due to worsening HF were only 5% at 6 months.

The importance of "Responders" early in the trials to accelerate completion of the trials -

I think it goes without saying that the cardiologist who recommends a patient for implant will be wanting that patient to be a "Responder" or even a "Super Responder" and not just less likely to be re-hospitalized within 30 days.

The cardiologist who sees their first one or two patients showing significant improvement after the implant is very likely to go on recommending further patients for implant even if some of these subsequent patients do not show the same level of response or any measurable response.

Conversely, the cardiologist who sees no improvement in the first one or two patients implanted might walk away from the trial and make no more referrals.

So these initial enrollments are extremely important for the success of the trial.

Get the start right and success is almost assured; get it wrong and the trial could languish for lack of enrollments.

Why inappropriate inotrope infusion therapy is creating confusion in applying selection criteria in the patient enrollment process

As discussed below in the Supplemental Information under the heading, "The penalty regime encouraging inappropriate provision of inotrope infusion therapy", hospitals are not uniformly applying American Heart Association (AHA) guidelines for the use of inotrope therapy infusion. See also "The role of Inotropes in treating Acute Decompensated Heart Failure", in the Summary Information section.

HF patients obviously will have varying degrees of need for inotropes. With the progressive nature of HF the degree of need will progress from, a stage of nil; to inotrope treatment in hospital for bouts of acute HF; to eventual total inotrope dependence in or out of hospital. A review of patient records should show the degree of dependence on inotropes of any particular patient.

But this is not so when the provision of inotrope therapy varies so widely. At one hospital a particular patient might be treated in hospital for an episode of acute decompensated HF and after stabilization be able to be sent home without inotrope therapy. At another hospital the same patient in the same circumstances could be discharged with continuing inotrope therapy infusion in an attempt to reduce or avoid the possibility of re-hospitalization within 30 days. And of course there can be degrees of difference in the application of inotrope therapy between these two extremes.

Obviously, this will make it difficult to determine the degree of inotrope dependence from a review of patient records.

Implications of determining actual degree of Inotrope dependence for the Counter HF C-Pulse trial

C-Pulse has shown in its Feasibility trial it can be quite successful in halting or reversing HF progression in patients for even those on inotrope therapy.

But C-Pulse is a heart assist device so it is not designed for patients whose hearts have deteriorated to the extent they are highly or wholly dependent on inotrope therapy for the heart to keep functioning.

Excluding all patients ever treated with inotropes would cause a hugely adverse and unnecessary reduction in eligible and suitable patients. Including all could result in treating patients totally unsuited for the C-Pulse therapy.

If selection criteria/rules are based on an assumption that a patient's past and present inotrope therapy has been provided in accordance with AHA guidelines then such a determination is subject to gross error where hospitals are not following the AHA guidelines.

I understand Sunshine Heart is addressing this issue by clarifying criteria for determining those patients on inotrope therapy but still suitable for enrollment. This should see a pick up in the number of enrollments going forward.

Implications of determining degree of Inotrope dependence for the Revive-IT HeartMate II trial -

HeartMate II is a full support heart assist device but because of its blood clotting, stroke and other risks is currently only approved for implantation in patients who are classed as inotrope dependent.

The current trial is to determine the safety of implanting in less sick patients than found in NYHA Class IV who are not inotrope dependent. Following the clotting concerns that arose last year, the emphasis is on implanting only the sickest patients in NYHA Class IIIb who are non-inotrope dependent. There is also a requirement that enrollment of patients be staged with review of results required before further enrollments. Included in the selection criteria are -

  1. ≤ 1 heart failure-related hospitalization within the previous 6 months, with no heart failure-related hospitalization occurring within the 30 days prior to study enrollment and up through randomization
  2. No history of inotrope use within the 3 months prior to study enrollment and up through randomization

Given the reported excessive use of inotrope therapy, it has to be asked how difficult it will be to enroll suitable patients out of the very sick HF patient population targeted.

Conclusions -

  • The Revive-IT trial appears likely to encounter far greater difficulties in enrolling patients (nil reported to date) than the Counter HF trial;
  • The actions taken and being taken by Sunshine Heart to accelerate enrollments going forward will likely bear fruit in the period ahead. These actions include a convening of a meeting of 40 physicians from 21 of the sites to clarify which HF patients are most suitable for inclusion in the trial, the issuing of clarification guidelines for selection criteria, and the recent hiring of Kimberly Oleson, former Vice President in charge of Global Clinical trials at Medtronic (NYSE:MDT) along with other support staff. Also, now that 13 sites are activated and recruiting, an advertising and marketing campaign for the trial is being launched;
  • It is likely this will quickly turn into a one-horse race with Sunshine Heart the uncontested leader in mechanical device therapy for NYHA Class III HF.

SUPPLEMENTAL INFORMATION

  • Thoratec's HeartMate II left ventricular assist device (LVAD);
  • Sunshine Heart's C-Pulse counter-pulsation system;
  • What heart failure is and its progressive nature;
  • What happens when optimal drug therapy (OMT) is insufficient;
  • The case for earlier intervention in HF with mechanical circulatory support devices;
  • The role of Inotropes in treating Acute Decompensated Heart Failure; and
  • The penalty regime encouraging inappropriate provision of inotrope infusion therapy

About Thoratec's HeartMate II left ventricular assist device (LVAD) -

HeartMate II is a full flow blood pump, capable of wholly taking over the heart's pumping function. It is inserted into the bloodstream in the left ventricle of the heart. The blood contacting nature of the device can lead to blood clotting, stroke, bleeding and other complications. This makes it a risky device and it is presently approved only for the very late stage HF patients in NYHA Class IV where the perceived benefits are considered to outweigh the risks. A feature of these patients is they will be wholly dependent on inotrope infusion therapy.

The Revive-IT trial, is a pilot trial which seeks to demonstrate that less sick HF patients in late stage NYHA Class III, and who have not yet become wholly dependent on inotrope infusion therapy, can be implanted with HeartMate II, with a resulting improvement in quality of life, without increasing mortality risk compared to HF patients on optimal medical therapy (OMT).

About Sunshine Heart's C-Pulse Counter-pulsation System -

The C-Pulse technology employs long proven counter-pulsation therapy applied extra-aortically and so outside the blood stream. This is a different, innovative, and far safer methodology than intra-aortic balloon pump (IABP) therapy which has been used highly effectively for decades. But IABP is highly dangerous like LVADS due to it being blood contacting. IABP can only be applied for short periods in a hospital setting to treat episodes of acute de-compensated HF. C-Pulse does not take over the heart's pumping function. Rather, its action increases blood perfusion of the heart muscle, lessens the workload and strain on the heart and also increases blood flow to the body. This provides a powerful combination of therapies, which together, assist a failing heart to recover. Because C-Pulse is a heart assist device it is not suitable for end stage HF patients where the heart requires the full flow support provided by a LVAD. It is therefore not indicated for HF patients who are wholly inotrope dependent.

In Sunshine Heart's C-Pulse's 20 patient feasibility trial, 60% of these NYHA Class III and ambulatory Class IV advanced HF patients improved by at least one NYHA Class (a very significant improvement in quality of life) and 25% of the 20 patient cohort have become asymptomatic for Heart Failure and have been weaned off the device.

This result is unheard of with drug therapy where generally the best that can be expected is a slowing in the worsening of the condition.

The NYHA Class III and ambulatory Class IV market targeted by C-Pulse is estimated at 5.2 million advanced HF patients in the US and EU. Only a tiny percentage of these patients have to be implanted to achieve multi-billion dollar revenues.

What Heart Failure is and its progressive nature -

  • HF is an ongoing inability of the heart muscle to pump sufficient blood for the body's needs. Onset of HF can result following a heart attack or from various other causes (see here)
  • Regardless of treatment, one-fifth of those diagnosed with CHF will die within one year and one-half will be dead within five years. Only about 20 percent survive much longer than 8 to 12 years -- a prognosis worse than most cancers. For those that do survive, quality of life is often severely compromised.
  • HF is progressive in nature. Current FDA approved drug therapy for earlier stage HF is only effective in slowing the worsening of the condition
  • The inevitable result is that eventually optimal drug therapy (OMT) becomes insufficient.
  • When OMT becomes insufficient the choices for a patient are either heart transplant, implant of an LVAD such as HeartMate II, or palliative care. Pending a decision, the patients go on to full time inotrope infusion therapy. Positive inotropes are powerful drugs that force the failing heart to work harder which is harmful to the heart. American Heart Association (AHA) guidelines require hospitals to use inotropes only as a bridge to more definitive treatment measures.

For further information on the above see my article, "Sunshine Heart's C-Pulse: The 'Platinum' Standard", and also here and here.

What happens when optimal medical therapy (OMT) becomes insufficient

When OMT becomes insufficient the choices for a patient are either heart transplant, implant of an LVAD such as HeartMate II, or palliative care.

LVADs are blood contacting pumps inserted into the left ventricle of the heart and powered via a percutaneous interface lead connected to a controller and battery pack worn externally. They are considered burdensome and dangerous for patients. The blood contacting nature of the device can cause clotting, strokes and bleeding and any interruption to operation is an immediate life threatening event.

So dangerous are LVADs that they are only currently approved for implantation where OMT has failed and the HF patient is classed as "inotrope dependent" and then generally only as a Bridge To Transplant (BTT).

HeartMate II is the only LVAD currently approved as safe enough to be used as Destination Therapy (DT), recognizing the need for this due to insufficiency of available donor hearts for end stage HF patients.

The Revive-It trial aims to determine if implantation of Thoratec's HeartMate II is warranted, based on safety and efficacy including improvements in quality of life (QOL), in less sick HF patients who have not yet become "inotrope dependent"

The case for earlier intervention in HF with mechanical circulatory support devices -

It has been widely recognized that earlier intervention with MCS would likely result in a better outcome for HF patients than waiting until they are desperately ill with end stage HF.

At the same time, the dangerous nature of LVADs meant, judged on a reduction in mortality risk alone, the use of LVADs was not warranted in less sick NYHA Class III patients.

A counter argument was, even if overall mortality risk was not sufficiently reduced, the quality of life (QOL) of a Class III HF patient might be significantly improved and in some case HF progression might be slowed, or halted, or even reversed.

In 2008, a working group evaluation by the National Heart Lung and Blood Institute (NHLBI) led to subsequent provision of funding support to the Revive-It trial to be carried out by The University of Michigan.

Much earlier, in 1999, Dr William Peters set out to develop a non-blood contacting heart assist device based on applying the principles of intra-aortic balloon counter-pulsation (IABP) applied in an extra-aortic manner. By adopting an extra-aortic approach Dr Peters intended to provide all of the benefits of IABP without the associated risks (see my article - "Medtronic And Sunshine Heart: Pacemaking And Counter-Pulsation - A Tale Of 2 Technologies").

This ultimately led to a 20 patient FDA approved feasibility trial commencing in 2008. The results, described above under the heading "About Sunshine Heart's C-Pulse Counter-pulsation System", certainly showed all of the benefits sought in the NHLBI sponsored Revive-IT trial without the mortality risks associated with LVADs.

The role of Inotropes in treating Acute Decompensated Heart Failure -

During the progression of HF, patients are hospitalized on an increasingly frequent basis with episodes of acute decompensated HF. In hospital they are able to be treated with a variety of drugs which can be quite effective in reducing symptoms. Included in the drugs are positive inotropes which make the failing heart work harder but are only meant for short-term use due to associated risks.

The table and quotation below from a Medscape article describes this in and out of hospital process and explains why it is not generally understood that a diagnosis of HF is just as serious as a diagnosis of cancer.

At Stage D, patients are considered to be at the end stage of the disease, and they select either extraordinary treatment interventions or aggressive hospice and palliative care.[1]

Despite the widespread recognition among providers that heart failure is a chronic and progressive condition, patients and families may believe that heart failure is a benign condition, even in the later stages.[11] In contrast to patients who have cancer and other diseases with a clearer trajectory, patients who have heart failure may have a poorer understanding of the disease itself and a lack of recognition that heart failure is a terminal illness at the end stage.[11] Difficulty accepting the fatality of heart failure may lie, in part, with the "roller coaster" pattern of exacerbations and remission, in which patients are able to bounce back after being near the brink of death.

For further information on the above see my article, "Sunshine Heart's C-Pulse: The 'Platinum' Standard."

The penalty regime encouraging inappropriate provision of inotrope infusion therapy -

Inotropes are a huge issue causing confusion and doubt in applying selection criteria for enrolment in the Thoratec HeartMate II Revive-IT Pilot trial and the Sunshine Heart C-Pulse Counter HF trial.

I went into considerable detail on the subject of inotropes in my article, "Sunshine Heart: Unexpected Buying Opportunity."

A summary of some of what I said on Inotropes in that article -

  • American Heart Association (AHA) guidelines require hospitals to use inotropes only as a bridge to more definitive treatment measures. C-Pulse is such a treatment measure;
  • The use of positive inotropes (parenteral inotropes and oral PDIs) in chronic HF has been consistently demonstrated to increase mortality. (see here)
  • The issue is that hospitals are increasingly supplying non truly inotrope dependent patients with continuing inotrope therapy infusion on discharge to reduce re-hospitalization rates.
  • This is driven by a 1% penalty for re-hospitalization within 30 days amounting to $280M in 2013 and that penalty rate will triple to 3% in 2015 (see here).
  • I believe that this use of inotropes by hospitals will come under increasing scrutiny and criticism.
  • C-Pulse is demonstrably preferable to inotropic therapy for reducing re-hospitalization rates for worsening heart failure

Caution: The information above is not intended to replace the advice of a doctor. I disclaim any liability for any decisions you might make based on this information.

Additional caution: As always, please do your own research before any buy or sell decisions. Use of information and research in the article above is at your own risk.

Investing in micro cap companies is not suitable for all investors and can be risky. It's important that investors thoroughly perform their own due diligence and analyze the potential risks. Due to illiquidity, share prices can fall despite strong fundamentals and possible inability to raise sufficient additional cash to continue to fund ongoing operations is always a serious concern. Fuller details of risks associated with Sunshine Heart as identified by the company may be found with their form 10-12B/A registration filing with the SEC and their other SEC filings.

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Source: Sunshine Heart: Turning Into A One-Horse Race In The NYHA Class III Heart Failure Stakes