Solving the Mysteries of Heart Disease
Page 31
Moreover, they changed the critical entry requirements established by the Surgical Therapy Committee. These guidelines determined which patients could qualify to enter the trial.
Essentially, all fail-safe mechanisms were ignored. These decisions were made by surgeons and cardiologists without experience in surgical ventricular restoration. These “leaders” were focused more upon easing the criteria for patient recruitment — than upon complying with the agreed-upon selection and procedure guidelines.
Expanding the quantity of participating centers was done to overcome their difficulty in getting sufficient numbers of patients to meet the entry guidelines. It is possible that these criteria were changed in order to retain government funding of this study. Of course, if such a financial maneuver occurred, it took place at the expense of discarding the established and successful standards set by experienced surgeons.
We objected. But our voices were not heard.
Separate from this, another issue developed. Before the trial, Connie Athanasuleas and I designed an alternative patch that could be used to rebuild the ventricle. It was not publicly available, had not been used by the RESTORE team, and was not being recommended for use by others. The trial leaders stated the patch would be fine, as long the STICH trial received all income from it.
Cumulative disagreements ultimately led to our resigning from the STICH Trial.
This was disappointing for us. Yet leaving STICH did not diminish our interest in Surgical Ventricular Restoration, which grew as the RESTORE Group’s activities continued. More and more successful ventricular reduction procedures were done.
However, the supervision of the STICH study, and its outcomes — only worsened after our departure.
Devastating Blow
The STICH results became highly flawed because of all the changes made by their leadership. Yet little could I predict how severely its parade of faulty and misleading data would negatively impact heart failure patients worldwide.
The STICH trial “statistics” showed that coronary grafting with ventricular restoration (501 patients) was no better than doing only coronary artery grafting alone (499 patients), judged by the patients’ after-treatment tolerance to exercise, re-hospitalizations for cardiac causes, and death rates.95
The implication was enormous — as these findings were now used to impede the worldwide use of ventricular restoration to treat congestive heart failure.
But how could its failure to work in the 500 STICH patients, overturn the highly successful ventricular restoration findings in the RESTORE Group’s 1,198 patients, and another 5,000 patients around the globe?
A powerful question. The answer is that everyone believed the STICH results — because this trial was funded by the esteemed NIH, and then reported in the well-respected New England Journal of Medicine in April of 2009. The world thus bestowed upon the STICH Trial a level of credibility that completely misrepresented the quality of the study — and its outcomes became accepted because of these sources. Yet no matter how prestigious the source of funding or reporting, accurate results are needed to make a legitimate conclusion. Without this, misguided conclusions are made — and patients with heart failure are deprived of an operation that can vastly improve their health and lengthen their lives.
Broken System, Battered Patients
The truth is, it is not at all difficult to recognize the flaws in the STICH study if one is willing to look. The purpose of my reporting them here is to make the reader aware that even a leading organization like the NIH, and highly regarded publications like the New England Journal of Medicine, are not perfect. Their status carries weight, but it is science that defines the truth. Evidence always wins.
For the trial to have validity, it first needs to have a proper selection of patients with the necessary medical condition, so that each surgeon can properly perform a procedure that will lower ventricular volume by more than 30%. (Achieving this reduction in ventricle size is what leads to patient improvement.) These guidelines were followed in the RESTORE Group’s 1,198 surgical ventricle restoration patients, and in the additional 5,000 patients worldwide whose outcomes matched the RESTORE results.89
But the STICH trial changed the qualifying criteria for both patients — and for participating surgeons — and so could not reproduce these positive findings. They then concluded that the previous 6,198 worldwide SVR outcomes were incorrect… by using their own STICH data.
The key question is: how credible is their data?
I will now show that the STICH trial execution failed to provide “credible data” by enrolling improper patients… by failing to achieve the required technical outcomes established by STICH’s own Surgical Therapy Committee… and by utilizing surgeons without experience in ventricular rebuilding.
These faults are not vague or subtle. They are glaring.
Selecting Improper Patients
Patients had to fit a series of entry criteria to be admitted to the trial — to match typical heart attack patients who then develop heart failure. So let’s see how those were met:
They needed hearts with a limited ejection fraction of less than 35%… yet a fifth of patients (19%) had an ejection fraction above that amount.96
They should have been excluded from the trial.
Ventricular volume had to be over 60 ml/m2 (and be measured again four months after SVR)… but nearly half of the patients (44%) never even had a volume measurement taken before and after the procedure.97
They should have been excluded.
A scar had to be present, and occupy 35% of ventricular perimeter… but nearly three-quarters of patients (73%) had no scar measurements taken before the procedure.78
They should have been excluded.
(This meant 73% of patients entered the trial without it known if they even possessed a ventricular scar. Imagine the torment of a surgeon cutting open the ventricle in a sick patient — only to find normal heart muscle instead of a scar! Yet such unneeded ventricular incisions were made into the non-scarred hearts of at least 19% of the patients. And their data was still included in the surgical ventricular restoration study!)
Of the only 27% of patients (267 of 1,000) that were checked for a scar — 46 had no scar — but were still kept in the study.78
They should have been excluded.
SVR is done for a scar after a heart attack — yet 13% of patients never had a heart attack.95
They should have been excluded.
9% of patients did not even undergo ventricular restoration — yet were still analyzed with this group.95
They should have been excluded.
How could such gross irregularities occur?
These problems stem from a failure to ensure that their own Surgical Therapy Committee standards were met, based on decisions made by the appointed STICH leaders (who, again, did not have any experience in ventricular restoration).
Remarkably, they issued new rules indicating that just looking at the external visual appearance of a poorly contracting heart provided enough evidence to do ventricular restoration — rather than documenting that an internal scar existed. This decision was completely incorrect, since the same outward appearance of poor contraction can simply be due to inadequate blood flow — and the ventricle should never be opened because of lack of satisfactory blood flow.
Improper Outcomes
The second major flawed area was in the assessment of the trial results, which had to meet certain conditions to be included in the evaluation. They are:
Ventricular volume (the ventricle size, determined by the amount of blood in the ventricle at end of contraction) needed to be measured to determine if the goal to shrink volume was achieved. But such volumes were not even measured in 44% of patients before and after the procedure.
Thus, how did they determine if the required amount of shrinkage was accomplished?
When ventricular volumes were measured, there was only a 19% reduction in their SVR group — significantly less than the
30% required to be part of the reporting data.
Those smaller volume patients should have been excluded.
Figure 2 compares the STICH finding of 19% volume reduction in 161 patient results — to the more than 40% average volume reduction in over 1,500 patients from the ten international centers that performed safe SVR procedures.94 STICH’s failure to achieve an adequate decrease in volume (more than 30%) demonstrates that the ventricular restoration procedure was inadequately performed.
Figure 2: Percent (%) reduction in ventricular volume in ten worldwide centers when surgical ventricular restoration is done properly, with an average 40% reduction shown in ten columns on left. Right column shows only 19% volume reduction in the STICH trial, a dramatic contrast.
Selecting Unqualified Surgeons
Given the poor surgical results just described, one must ask: how could this happen? That answer is easy: as cited earlier, the study utilized surgeons without experience in rebuilding ventricles. The basis for this decision likely springs from STICH expanding the trials to take place in 127 worldwide centers from the initially selected 50 centers — in order to increase availability of test sites to acquire sufficient numbers of patients (and in doing so, ensure that the study would receive the financial support to continue).
But surgeons in these centers were not trained in this procedure. When our RESTORE Group began their trials, I went to different centers that would be performing the procedure and helped them learn how to do surgical ventricular restoration. With the STICH trial, the Surgical Therapy Committee had planned to do the same thing in the 50 centers originally chosen — but none of this was done after our departure from the study.
So there was no assurance that surgeons participating in the study had met the requirements of having already done this procedure on at least five patients — to demonstrate they could successfully reduce ventricular volume by at least 30%, increase ejection fraction by 10%, and have less than 10% mortality.
Consequently, operations were performed by surgeons who had never done this procedure before. Plus, given that 127 centers now participated, there would only be an average of four SVR cases conducted at each center. …A very steep learning curve for a surgeon to effectively learn a new treatment.
Ultimately — recruitment, rather than competence — won the day. The study became a gigantic charade.
Consequences for the Heart Failure Patient
Unfortunately, the consequences of this flawed data and its analysis were used by the cardiology and surgical communities to substantiate their belief that ventricular restoration had no advantages over present methods (coronary bypass grafting and mitral repair only).
The statisticians summarizing STICH trial results made conclusions from the data they were given, but that data was not valid.
Regrettably, this data is still considered sacrosanct because it emanates from distinguished sources (NIH, New England Journal of Medicine). It guides clinical decisions in the vast population of heart failure patients, and unfortunately, prevents them from receiving the ventricular restoration procedure that will help them.
Attempts to Bring the Light of Truth… Go Dark
In an attempt to counter the study’s misleading results, we asked the New England Journal of Medicine if we could write an editorial to formally respond to the published STICH report. But they would only allow us to write a brief letter to the editor.98 We also placed reports in other major journals, but nobody listened, and thinking has not changed.99
Randomized Trials
People would sometimes argue that our RESTORE Group results were not part of a prospective randomized trial. Everyone believes that credibility can only come from a randomized study.
Yet history is a wonderful teacher, as many stories repeat themselves.
A prospective randomized trial only has validity if the selection criteria are met and all procedures are done properly. This lesson was notoriously played out in the 1980s, when the role of coronary artery bypass grafting was first being defined. The VA Hospitals did a prospective randomized trial in 13 centers, and found that coronary bypass grafting was no better than other medical treatment. They reported an approximate 6% mortality and found that many grafts had closed, and concluded that coronary grafting was unnecessary.100 This is in line with the way the STICH trial concluded that SVR was not helpful.
It turned out that these poor results following coronary bypass grafting occurred because the surgeons at participating centers had performed an inadequate technical procedure. This flaw became evident when Fred Loop at the Cleveland Clinic posed a powerful counterargument.101 He summarized results from 1,000 consecutive patients at his center and showed mortality was approximately 1% and graft closure was rare. The contrasts were astounding, as this rebuttal became globally accepted and the world of coronary bypass grafting exploded. It became the standard method of treatment for coronary artery occlusion (blockage). The lesson was blatantly clear: a prospective randomized trial does not work if you do not do the operation right.
To me, a natural parallel exists between these two studies. In one, if an open vessel is closed… open it. In the other, if the natural elliptical shape becomes a sphere… bring back the ellipse.
The Impact and its Meaning
The hardship of this failed STICH study does not fall on me or on members in the RESTORE Group, but upon the thwarted opportunity of the medical community to counter the world’s most debilitating illness and on the patients it could have helped. The STICH trial’s faulty results was like “placing nails into the coffin” — one used to bury a revolutionary treatment for this devastating disease.
This experience made my thoughts drift back to when I applied to medical school and talked about my favorite book, the story of Philippe Ignaz Semmelweis, who had said, “Wash your hands to prevent the spread of childbed fever.” This truth was ignored. Certainly, “returning the dilated heart to its natural elliptical shape” aims at a similarly powerful objective.
When the STICH trial was being planned, a famous cardiologist met with me to say, “Gerry, if this treatment works, it will place a crowning plume upon your accomplishments.” My response was that my prize is, “If no one else experiences my dad’s debilitation when he died from the ravages of end-stage heart failure, nothing else is needed.”
For that reason, I will keep trying to hasten its arrival.
The Matter of Time
One step in the right direction came when the limitations of the STICH trial became apparent in Europe.102
According to their 2010 Task Force, guidelines from the European Society for Cardiology (ESC) and European Association for Cardiothoracic Surgery (EACTS) contradicted the STICH conclusions — and recommended the consideration of using SVR in centers with high levels of experience — following proper measurement of ventricular volume and the culprit scar in potential patients.
Aside from these welcome scientific comments coming from Europe, the STICH trial continues to represent a huge tragedy in how health care procedures are delivered. Because of its flawed data, the report remains an enormous obstacle to the proper treatment of the international population of heart failure patients. These misguided findings have essentially stopped cardiologists from considering having the spherical, failing chamber rebuilt back to its natural elliptical, healthy functioning form.
Truth will eventually win, but the huge number of sick patients with failing hearts will unfortunately bear the brunt of the STICH report’s marred data. They will continue suffering the devastating symptoms and unchanged death rates from heart failure until this calamity is overturned.
This distressing chain of events was properly summarized by Mark Twain: “A lie can travel halfway around the world while the truth is putting on its shoes.”
It is time for the truth to be heard — and acted upon.
CHAPTER 18
Paco: Exploring the New Horizon
Some discoveries reverberate throughout the scientific com
munity. Revelations by Albert Einstein and Sir Isaac Newton have altered thinking forever. The key to their power is simplicity. We will now learn of a third such revelation.
Each of our prior chapters has described a research adventure in which I was fortunate to chase after breakthroughs in critical areas of cardiac care, ranging from heart-protecting cardioplegia, to countering heart attacks, to healing heart failure. Each undertaking focused primarily on finding an innovative treatment for a particular condition.
This chapter’s exploratory voyage is one that would change everything.
Many things we had learned before would now come into question. We were sailing onto an ocean that had never been crossed, with no buoys to guide us. Now that can be frightening. But I was not tentative because my curiosity compels me to find answers.
It is an exciting way to travel through life, and reflects how I have always lived mine.
This chapter is about navigating waters that would alter the future of the entire cardiovascular field… by unraveling a truth that has escaped detection throughout the ages.
Riddle of the Heart
Everything in nature has a reason for being as it is. From the massive spiral formations of our galaxies to the crystalline configurations of a snowflake, there is a governing pattern. This is also true for the heart.
Our heart is nothing less than miraculous. Consider that it beats more than 100,000 times a day, over 35 million beats a year, pumping blood (with help from squeezing arteries and veins) through blood vessels over 60,000 miles long.
Though the heart’s accomplishments are clear, opinions about how it achieves them differ, even with all of today’s technology that might explain it. This impasse continues due to a lack of agreement on how its movement during each heartbeat can be explained by its structure. It’s a basic question — a puzzle you might expect to have been solved long ago.