Is sacubitril a "game changing" breakthrough or approved on basis of a stacked deck trial or something in between?

A  number of medical commenters and pundits have claimed game changer status for sacubitril but also the trial that lead to its approval has been accused of being not a fair test. Two general types of the tricks of the trade that can be employed to make a comparison between treatment better than it really is  are 1) stack the desk and 2) cook the books (AKA  various sometime obscure statistical slights of hand)

In this instance I cannot comment on the second but others have suggested that there was at least a little bit of deck stacking.

Lets look and what was compared with what.

The drug that the FDA approved  is named Entresto and is a combo pill consisting of a first in class drug named sacubitril and valsartan which is a  well proven Angiotensin receptor blocker which has been proven effective in the treatment of heart failure (HF), Sacubitril inhibits neprilysin which in turn is a inhibitor of natriurectic  hormones .The new combination pill is named Entresto.

Entresto was compared with the ACE inhibitor,enalapril.

If someone wanted to determine if the addition of sacubitril  to valsartan was safe and effective and better than valsartan alone why not compare that combination with valsartan ?. Why choose a drug from a different class than valsartan?

 In the ParadigmHF trial, 8442  patients with class 11-IV NYHA heart failure with ejection fractions less than 40%. were treated with either Entresto or with  Enalapril at a dose of 10 mg twice a day.

 So how big was the difference between the two treatment groups? 26.5 % of the control group versus 21.8% of the enalapril treatment group were hospitalized for heart failure. A difference to be sure but enough of a difference to be heralded as a game changer?


But there is as usual more to the story- now there are expressions of concerns about some unusual potential side effects of the breakthrough medication involving some breakthrough complications in  the eye and the brain.see here

Also see here for a JAMA commentary about the concern of a potential increase risk of Alzheimer disease  by inhibiting the action of neprilysin in its putative  role in amyloid degradation. Not to worry though- a projected trial to look into that issue should be ripe for publication circa 2022. See here for a further  discussion of some criticism of the trial including how externally valid is it (how well does it represent real life treatment of HF) and how representative was the dose of the comparative drug.

 Larry Husten  comments on the number of "game changers" in cardiology in 2015 in his posting entitled " 2015 the year we finally cured heart disease".

No replay of the 1914 Chistmas truce in Iraq on this Christmas day

The story of the 1914 ad hoc ,from the bottom up  temporary truce on Christmas day during World War 1 is well known and can be read about in detail here.

This story from the blog site Antiwar.Com tells of deaths in Iraq thought due be due to targeting Christians apparently including some nuns. Of course there is a big difference, France and England  were nominally  Christian countries and both the British and the Germans soldiers had shared very similar Christmas memories from childhood .

Here we just have the unending, unforeseen consequences of just trying  to  "bring Democracy to the Middle East"  of the incredibly bad idea of the war in Iraq.

Will just 2-3 hours of aerobic exercise a week prevent your heart from getting stiff?

With the requisite,appropriate,cautionary,more-work- is needed caveat the authors of a very detailed and elaborate study published in 2014 say that 4-5  one half hour exercise sessions per throughout adulthood will prevent most of the  age related loss of  the  heart's compliance and distensibility .In other words that amount of aerobic exercise will help to prevent the heart chambers from getting too stiff.It would really be nice to think so.

So what is wrong with stiff cardiac muscles ?

Application of the Woody Allen axiom of the pathophysiology of aging tells us that as we get older everything that should be soft gets stiff and everything that should be stiff gets soft.Think lens of eye,arteries and joints to name just a few.

A stiffer left ventricle is not a good thing as far as cardiac function is concerned.

The left ventricle (LV) basically sucks in blood while filling ( diastole) and ejects it during systole.As the heart becomes more stiff, the ventricle fills less easily , less sucking and more push from the atrium.The term diastolic dysfunction refers to this. Diastolic dysfunction (DD)  plays a role in a number of heart diseases and some degree of DD is arguably a "normal" process of aging or as the authors of this article imply "sedentary aging".


Researchers  the Institute for Exercise and Environmental Medicine  in Dallas recruited   healthy subjects over age 64 and screened them for histories of lifetime exercise habits and divided them into four group of about 25 per group.There were sedentary folks with no more than one exercise session per week , those with 2-3 session per week (causal exercisers), those with 4-5 sessions per week, labelled "committed" and the competitive group who trained 6-7 times per week and took part in races. (See here for full text of article) (This group lead by DR. B Levine from Southwestern Medical School has published a number of articles on general topic of cardiac function changes with aging and diastolic dysfunction. )

Extensive physiological tests were done including some involving right sided cardiac catherterization  to measure the  pulmonary capillary wedge (PCW) pressure.  (I am still amazed that they found 100 healthy people who agreed to let some one put a catheter in their pulmonary artery for non-therapeutic reasons).  PCW pressure is believed to be a reasonably accurate measure of the pressure in the left atrium which reflects left ventricular pressure , and elevation of which is a measure of LV failure.By infusing saline IV they were able to obtain curves relating the LV volume at the end of diastole with PCW pressure providing an indicator of LV compliance and distensibility.

The committed exercisers' values for these measures of ventricular compliance were very close to those of the competitive exercisers and definitely better than the sedentary and casual exerciser group as were values for other measures such as maximal oxygen uptake. This data ( shown in their "Central Illustration",p 1263 constitutes the major evidence  for their thesis regarding how much exercise one has to do to maintain some semblance of LV distensibility. The more exercise the less stiffness but what the casual exercisers did was not enough.

 Decrease in LV compliance and distensibility characterize heart failure with preserved  ejection fraction (HFpEF). Other work by these same authors have shown similar pressure volume relationships in patients diagnosed with HFpEF as those seen in the sedentary and casual exerciser groups.They argue that sedentary aging  "sets the stage for this increasingly recognized form of heart failure" It should be noted that heart failure with  preserved EF might more correctly be named HF with preserved EF at rest. The EF does not increase normally with exercise in HFpEF and exercise intolerance is a major feature.

How the stage is set is unclear. Studies of exercise programs in patients with heart failure show improvement in exercise capacity  but do not show improved values for various tests of diastolic function or ,for that matter-ejection fraction. So the improvement seems to occur in the muscles with increased capacity to extract oxygen for muscle function.  Here the oxygen uptake would improve while cardiac output may not -they are able to exercise more because their muscles are better able to extract the oxygen from their limited cardiac output.Remember the Fick equation ( V02=CO X A-V 02 difference).

 There is more to ventricular filling than ventricular compliance- how rapidly the heart muscle can relax following the ejection or systolic phase of the cardiac cycle is important. One aspect of relaxation can be measured by the IVRT ( isovolumic relaxation time) ,This can be measured by the time between aortic valve closure and mitral valve opening. The IVRT and the IRCT ( isovolumic contraction time) both increase as a function of age and are apparently not favorably influenced by life long aerobic exercise.

I have a high school friend who quoted one of his football coaches who was fond of saying "you are only as young as your legs".So some threshold value of regular aerobic exercise may serve to keep the ventricles from getting too stiff while exercise after the onset of HFpEF may still help but this time by  making the legs a little younger.

Marathon running and pacemaker safety

A Dutch group evaluated pacemaker function and safety in nine long distance runners  training for and participating in marathons.The full text article is available.

Here are some of the highlights:

The investigators recruited nine runners who had pacemakers (PM)by sending questionnaires to several Dutch pacemaker centers.

The program consisted of a nine month training program with supervision by running coaches,cardiologists ,pace maker technicians and representative from Medtronic, one of the projects sponsors.(Adidas was the other sponsor)

Pacing and sensing systems were testing during the training and the actual races  ( marathon and half marathon) and no problems were found.The Polar heart rate monitor system was tested as well and in all but one case functioned well without PM interference.A running chip ( Champion) was also tested and found free of interference with or from the PM.

Six had a DDD pacemaker and three a VVIR. (see here to decode the abbreviations)

 Only four of the nine were paced continuously.Three were well trained young athletes  who had PMs because of episodes of asystole and their PM were basically on standby and there was no PM stimulation during training or racing. None had a bi-ventricular PM ( i.e. cardiac re synchronization therapy or CRT)

For those  running with complete heart block the upper pacemaker rate had to be adjusted up to 170- to 180 to maintain 1 to 1 atrial ventricular synchronize during very high heart rates.

For runners who for various reasons develop the need for a PM the report is basically encouraging and good news for runners who need a PM and who want to continue running, even , at least for some- long distances..

But my Cassandra-like side has to wonder if those who were continuously paced and who run a lot ( I believe they all have right ventricular pacing)  might be a risk for the putative deleterious remolding and hypertrophy that a number of long time RV apical  paced patients develop. (See  here for a detailed exposition of Heart failure developing in patients paced from the Right ventricle and the pathophysiology involved.).

There was a two years followup by survey that  showed no evidence of a PM malfunction but I do not believe any cardiac function testing was done.

Left Bundle Branch Block (LBBB) is not just a EKG finding, it is a really big deal

The EKG pattern of left bundle branch block (LBBB) has been known for decades and that pattern was considered an indication of heart disease. In Dr. George Burch's text book, written over fifty years ago, A Primer of Heart Disease,  I read that LBBB was a pathognomonic sign of heart disease.

However,at the time, It was not known what was the role of LBBB  in altering cardiac function.Did it cause heart disease- this point is debated still. Did patients with heart disease and enlarged hearts develop LBBB or similar EKG patterns as their disease progressed? Some patients have LBBB secondary to coronary artery disease and an infarct involving the interventricular septum,some have heart failure and some  "just" have a LBBB, the so called lone  or isolated LBBB.

 We know the following about the cardiac functional consequences of LBBB in patient with lone LBBB:

1) Abnormal movement of the interventricular septum early in cardiac contraction ( systole) ie in the pre-ejection phase the septum moves to the left.

 (In most cases the septum moves to the left while lateral left ventricular wall relaxes.The septal movement is observed with cardiac echo and termed as "septal beaking")

2) delayed contraction of the left ventricular wall) reduced ejection fraction (EF)

4) Impaired filling of the left ventricle (diastolic dysfunction)

5) More time wasted with the heart valves  closed ( Technically  measured as prolonged IVCT and IVRT) and measured by the MPI or myocardial performance index (See end note 1)

6) Mitral regurgitation due to asymmetrical contraction of the papillary muscles

7) increased in left ventricular end-diastolic  pressure

8) Increased pulmonary artery pressure during exercise in some patients with normal resting echo

9) impairment of the normal ventricular twisting motion

Basically the right and left ventricle are designed to contract at the same time. In LBBB they do not- the right contracts milliseconds before the left.So there is inter-ventricular loss of synchrony.

The heart's electrical wiring system is designed so that the impulses that cause muscle contraction spread out more or less simultaneously from the two bundle branches. In LBBB the activation pattern is markedly altered so that the  septum is activated from right to left with early septal activation and contraction of septal area during the isovolumic contraction phase of systole and  there is delay of  the impulses arriving  at the lateral and posterior left ventricular wall delaying muscle  contraction.

There is also asynchrony within  the left ventricle  apart from that of the septum and lateral wall being out of sync. Various segments of the Left ventricle  also do not contract as an organized system , some segments contracting and relaxing out of tune with others.This is referred to as intra-ventricular  dysynchrony.

Consider what the development of LBBB does to an otherwise healthy heart and consider how that effect would be more manifest clinically in a diseased heart with failure.

Two studies have shown that the ejection fraction decreases about 10-15%. while another reported only 5.8%. The EF does not tell the whole story as there is also impaired filling of the left ventricle.So not only is the stroke volume diminished by a lower EF but impaired filling leads to less blood to eject.Cardiac output falls and is particularly evident during exercise.

Details regarding cardiac function in patients with LBBB and normal coronary arteries ( most were shown not to have coronary artery disease by angiography) were provided by Ozdemir who studied 45 cases of isolated LBBB ranging in age from 48 to 72.(Effect of isolated left bundle branch block on systolic and diastolic function of left ventricle),  see ref 3 below.

Although the ejection fraction was reduced  "only" 5.8% from controls,there were statistically significantly higher values in the LBBB group  for the left ventricular end-systolic diameter,and the isovolumic relaxation  time and the isovolumic relaxation time and importantly the invasively measured ( done at the time of  coronary angiography)left ventricular end- diastolic pressure ( 14+/-3 versus 10 +/-3) with a normal of 3-12.Earlier work had shown that some patients with "Lone" LBBB -those with no coronary artery disease or obvious heart failure- may have normal or nearly normal  echocardiograms ( but typically have evidence of impaired relaxation on Doppler mitral flow studies) and may  have  clinically significant increased pulmonary artery pressure with exercise.

With increases in the IVRT and IVCT there is less time for the ejection time which leads to an elevated or abnormal MPI ( myocardial performance index).The failing heart  both contracts and relaxes more slowly and the MPI has been proposed as a useful prognostic indicator. There is more time spent with the aortic and mitral values in the closed position leaving less time for the basic work of the heart , which is  ejecting blood, to occur.But in lone LBBB it is not the muscle cells defects that are the problem but loss of the normal incredibly well coordinated contraction and relaxation of the ventricles.

I can add a personal story. When I  recently developed a LBBB my "comfortable "( age appropriate and consistent with what one might expect in an aging runner)  jogging times increased from about 12: 45 minutes per mile to 14 +  minutes per  miles. which represents a 12% decrease. in running speed. Similar stories can be found on the web describing what LBBB does to a person's exercise capacity. It should be noted that all patients with lone LBBB do not have the same cardiac functional impairment nor the same rate of progression of impairment.

But there is more to the functional consequences of LBBB. Some patients  ( many, most ?) with LBBB develop heart failure after a variable lag period. Some of the evidence for this occurrence comes from the clinical experience of patients with heart block who have had pacemakers with the traditional right apical pacing electrode, which in effect is an iatrogenic  LBBB.It is thought that the abnormal contraction patterns due to LBBB may lead to a deleterious cardiac remodeling and ultimate heart failure.  

The introduction and advances in cardiac echocardiography made it possible to gain important insights into what are  the functional consequences of LBBB  and ultimately provided a new treatment for heart failure.

Dr.  IG McDonald in 1973 demonstrated by echocardiography that the interventricular septum moved abnormally. The septal problems were defined more clearly by Curtis in 1983 who showed that various abnormal movements of the septum were associated  with lower cardiac ejection fraction.,some patterns being more detrimental than others. Curtis mentioned that cardiac pacing might mitigate the LBBB induced abnormal ventricular contraction pattern.

 "The early studies described how the abnormal and/or delayed left ventricular activation wave front could lead to a reduction in left ventricular efficiency and performance that is largely independent of myocyte contractile function" Ref 1 see below.

Chaper 7 In Ellenbogen fifth edition of  "Clinical cardiac pacing,defibrillation and resynchronization therapy" quotes a 1974 article by Takshita et al as providing the first direct evidence for an effects of LBBB on LV function (6) in patients with intermittent LBBB.

 But it was not until 1994 that his theorizing was proven true when two clinical  studies demonstrated that pacing targeted to the site of the most delayed left ventricular contraction could improve overall cardiac function. The dyssynchrony could be "fixed" by resynchronization  ( or at least could  provide an effective work around) which became known as CRT or cardiac re-synchronization therapy.( also known as Bi-ventricular pacing, or Bi-V as most CRT is accomplished with Bi-V although more recently there is increasing use of His Bundle Pacing in re-synchronization therapy) .About 1/3 of HF patients treated with CRT do not show improvement, the 2/3 who do are those with  LBBB because in them the dyssynchrony is a major factor in the cardiac impairment and is often improved with Bi-V.

Cardiac pacemakers are nothing new-the first totally implementable pacemaker (PM) was introduced in 1958 and for decades were used to treat patients with heart block .Now a new use for pacing has improved the outlook for many patients with heart failure. It turns out that that the ones benefited are those with LBBB- so would not patients with lone LBBB also benefit from CRT? Is it necessary for a patient with LBBB to develop overt heart failure before pacing is considered or could/should the patient with NYHA class 1 be offered the implant?What about the patients with normal cardiac echo studies and shortness of breath on exercise? On further thought if a patient with LBBB has shortness of breath I would not expect the echo to be perfectly normal.The EF might not be less than the lower limits of normal but there would at least be delayed relaxation evident on echo . and perhaps septal flash .If PM implantation were a completely benign procedure the answer would be easy.

Endnote 1. IVCT is the isovolumic contraction time and the interval between mitral valve closure and aortic valve opening.IVRT is the isovolumic relaxation time and is the interval between aortic valve closure and mitral valve opening 

References:

1)Breihardt,G,and Breithhardt ,O "Left Bundle  Branch Block-an Old-New Entity". J of Cardiovasc Trans. Res. 2012 5: 107-116

2)Grines,CL et al, Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony.  Circulation 1989. 79:845-853

3)Ozdenir,V Effect of the isolated left bundle branch block on systolic and diastolic functions of left ventricle. J Am Soc Echocardiog, 2001 Nov 14, 11 , 1075-9

4) Vaillant, C Resolution of Left Bundle Branch Block-induced cardiomyopathy by cardiac

 resynchornization therapy. J. of Amer College of Cardiology.2013, 61, 1089-1095

5)Yu,cm et al Biventricular pacing in patients with bradycardia and normal ejection fraction. NEJM 2009,363

6) Takshita, A Effect of intermittent  Left bundle branck block on left ventricular performance. AJM 56:251, 1974 (no abstract available on Pubmed)

addendum 12/28/15. Minor editing and addition of a 9th abnormality in LBBB,.

addendum 1/17/16 minor editing.5/22/16 Several spelling errors corrected.

addendum 3/19/17 Three sentences were added to the last paragraph.

addendum 10/12/17 more superfluous fiddling with the wording in several places

Addendum 12/3/17 Mention of His Bundle Pacing added

Addendum 6/2/2020 Takskhita Reference on functional changes in intermittent LBBB added

Was the clinical trial that lead to the approval of Rivaroxaban for A Fib flawed?

The Rocket -AF trial was key in obtaining FDA approval for rivaroxaban, ( Xarelto) in part because of the decrease bleeding  in the riva group versus the warfarin group, at least in terms of fatal and intracranial bleeding. It was shown to be non-inferior in regard to stroke prevention.However, questions have been raised about the devices used  to measure to monitor warfarin therapy. It has been alleged that the instruments had a tendency to give falsely low values for the INR. If so , one wonders if the physicians  whoever monitored it would then increase the warfarin dose   to reach the target INR and that might account for the higher bleeding rates in the warfarin group or a relatively lower rate in the rivaroxaban group.

 The warfarin control arms of these trials can be problematic.There is always the issue of what percentage of time were the patients in the target INR range.Further ,heaven forbid, there may be even opportunities  for stacking the deck.

There is still more drama to the story -the FDA panel that reviewed the data did not recommend its approval but the full deciding body at the FDA voted in favor. Some has also expressed concern about the current leading candidate  for the head of the FDA since he was a prominent investigator in the trial.

We may never know  or if we do it may take a while to sort that out, Meanwhile what about all the folks taking Xarelto? Can they be confident that this new or novel anticoagulant affords them greater safety than  warfarin?Should they consider switching to apixaban? Should they even worry , after all there have been other trials that demonstrated efficacy and safety in the setting of venous thromboembolism and for prophylaxis in hip replacement.

More details can be found at Larry Huston;s excellent site  "Cardiobrief". He also raises the issue of possible COI with the candidate for the Head Of the FRA, Robert M Califf who was a principal investigator in the Rocket-Af trial. As usual Dr Roy Poses offers important insights into the issue of COI and the  ever spinning revolving door in health care in regard to the Dr. Califf and the unprecedented endorsement  of him for the FDA post by the editorial folks at the NEJM.See here.

 12/13/15Addendum; The folks who did the Rocket-af say they have now checked into the matter and that there is no need to worry. Sort of a move along nothing to see here type statement.  Unfortunately  they have not yet made public the data they collected and used to reach that reassuring conclusion. Stay tune.See here for details  from the blog Cardiobrief by Larry Hustin which as usual has a wealth of useful information from the world of cardiology.