Verslag Stage Wetenschap Can a minimally invasive HVAD...

Verslag Stage Wetenschap

Can a minimally invasive HVAD implantation become the new gold standard in advanced heart failure treatment?

Student: Philipp Robin Ahrens

Student number: 1949594

External attendant: PD. Dr. med. J.D. Schmitto

HTTG (Department of Cardiothoracic,

Transplantation and Vascular Surgery)

External Institution: Hanover medical school (MHH)

Germany

Attendant of home university: Dr. R.A. de Boer

Cardiologist

Home Institution: Groningen University Medical Center (UMCG)

The Netherlands

Research period: 30.06.2013 – 17.11.2013

Date of dispatch: 26.12.2013

Verslag Stage Wetenschap Philipp R. Ahrens

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Abstract

Heart failure is a major cause of death in developed countries. Today cardiac transplantation is frequently considered the best possible treatment for end-stage heart failure once standard therapy has failed.

Cardiac transplantation has well known risks and disadvantages, availability of donor organs being one of them. For people awaiting cardiac transplantation the mortality rates at one and five years are respectively 30% and 50%; clearly there is an urgent need for alternative treatment options. (1,2)

With more than 50 years of technical engineering research in this field, potential alternatives to cardiac transplantation have become available. Mechanical circulatory support (MCS) being one of them. Implantation of a left ventricular assisting device (LVAD) has evolved from use as a bridging technology whilst awaiting transplantation, to a longterm treatment option for end-stage heart failure. Unfortunately the implantation procedure is associated with a high rate of complications and is therefore limited to severely ill patients only.

The most recent evolution of surgical LVAD implantation is a novel technique employing a minimally invasive left-sided anterolateral thoracotomy instead of a full sternotomy. With this novel technique complications can possibly be reduced and this therapy option could become available to the broader population.

In this study I compared the conventional technique with the novel minimally invasive technique in terms of survival and overall outcome. My findings suggest that the novel technique is superior compared to the conventional method and may even offer an alternative to heart transplantation.


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Table of Contents

Abstract ................................................................................................................................. 2

List of abbreviations .............................................................................................................. 4

1. Introduction .................................................................................................................... 5

1.1 Hypothesis ................................................................................................................. 5

1.2 Endpoints ................................................................................................................... 6

2. Presenting the Left Ventricular Device ............................................................................ 7

2.1 History ....................................................................................................................... 7

2.2 Device........................................................................................................................ 8

2.2.1 The HVAD® Pump ..................................................................................................... 8

2.2.2 Technology Pipeline................................................................................................... 9

2.3 Surgical Technique ...................................................................................................10

2.3.1 Conventional HVAD implantation ..............................................................................10

2.3.2 Minimally invasive HVAD Implantation ......................................................................12

3. Material and methods ....................................................................................................14

3.1 Study Design ............................................................................................................14

3.2 Study Population .......................................................................................................14

3.2.1 Statistical Analysis ....................................................................................................14

4. Results ..........................................................................................................................16

5. Discussion .....................................................................................................................24

6. Conclusion ....................................................................................................................29

7. Nederlands samenvatting ..............................................................................................31

References ...........................................................................................................................32


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List of abbreviations

ALIDA Arzt- und Leistungsstellen unterstützendes Informationssystem der digitalen Archivierung

BMI Body Mass Index BPM Blood Pressure Median BSA Body Surface Area BTT Bridge to Transplant CCS Canadian Cardiovascular Society CCS IV Inability to perform any activity without angina or angina at rest,

i.e., severe limitation Critical State Ventricular Tachycardia or Ventricular Fibrillation or Aborted

Sudden Death, preoperative Cardiac Massage, preoperative ventilation before anesthetic room, preoperative inotropes or Intra Aortic Balloon Pump, preoperative Acute Renal Failure (anuria or oliguria <10ml/hr)

ECC Extracorporeal Circulation ECMO Extracorporeal Membrane Oxygenation eGFR Estimated Glomerular Filtration Rate GSH General State of Health Hb Hemoglobin IABP Intra Aortic Balloon Pump ICU Stay Intensive Care Unit Stay postoperative in days LA Left Atrium (normal = 24-40mm) (3) LVAD Left Ventricular Assisting Device LVEF Left Ventricular Ejection Fraction (normal = 55-70%) (3) LVEDD Left Ventricular End-Diastolic Pressure (normal = 36-56 mm) (3) LVESD Left Ventricular End-Diastolic dimensions (normal = 20-40mm)

(3) MCS Mechanical Circulatory Support MTPG Mean Transpulmonary Gradient NYHA NY Heart Association Classification PA Pulmonary Artery (normal = systolic 15-30mmHg, diastolic 4-

12mmHg) (4) PCWP Pulmonary Capillary Wedge Pressure (normal = 2-15mmHg) (4) PI Pulsatility Index Post Stay Postoperative Stay at the Hospital in days PVR Pulmonary Vascular Resistance (normal = 20-130 dyn·s/cm) (4) Recent MI Myocardium Infarction within the last 90 days RA Right Atrium (normal central venous pressure = 3-8mmHg) (4) RCT Randomized Controlled Trial RV Right Ventricular (normal = systolic 15-30mmHg, diastolic 3-

8mmHg) (4) SHF Seattle Heart Failure Score SVR Systemic Volume Resistance (normal = 700-1600 dyn·s/cm) (4) VAD Ventricular Assisting Device


1. Introduction

Ischemic heart failure is one of the major causes of death in developed countries. (5) This is a serious life threatening condition resulting in decreasing heart function and eventual circulatory compromise, which may result in severe complaints, morbidity, and mortality. Recent epidemiological data have predicted that the number of cardiovascular patients worldwide will rise to more than 7 million by 2020, with heart failure being a main culprit. (5) There still is no cure available for heart failure, medication is the first choice of treatment as pharmacological care has improved considerably over the past decades. Unfortunately this non-invasive treatment depends on a “reactional” heart muscle, which is no longer present in patients with severe (end-stage) heart failure. Other treatment options include cell-based therapy, gene therapy and potential refinement of current therapy based on genetic variations. Although these options are very promising for the future they are still under development and nowhere near the gold standard Cardiac transplantation, being the ultima ratio treatment still presents the best option for patients with end-stage heart failure, with the best survival rates. (6) Unfortunately the cardiac transplantation is dependient on the donation of human hearts. The availability of these organs is not nearly close to the number of patients in need of sufficient treatment options. Within the past 50 years another treatment option has been developed, which is now used worldwide: mechanical circulatory support (MCS). Over the years there has been a diversity of different machines that support the human blood circulation. There have been total artificial hearts and machines that support only one ventricle. The left ventricular assisting device (LVAD) has shown the most promising results. Today there are many very different left ventricular assisting devices available for implantation. The HVAD from HeartWare is smaller than most and the only LVAD that is being implanted at the Medical School Hanover (MHH) in Germany using two different surgical approaches. The focus of this study lies not on the functionality of the HVAD itself, but on the implantation technique. In 2011 the novel minimally invasive approach was introduced at the MHH and is since then used more often then the conventional total median sternotomy technique. How this novel implantation method is superior to the worldwide used median sternotomy will be established in the following chapters.

1.1 Hypothesis

This study is focused on the effects for the patient of a novel implantation technique of HVAD (HeartWare ventricular assisting device), in comparison with the conventional complete median sternotomy. In order to compare the two different approaches, various aspects are evaluated.

I expected that the novel approach would lead to a better overall outcome. This expectation is based on earlier studies comparing conventional surgical techniques with minimally invasive techniques. Schmitto et al. have shown that the described minimal invasive technique leads to promising results, which are now to be proven by a bigger population. (4) It is tremendously important for these seriously ill patients to have a fast recovery. The longer these patients have to stay in bed in the hospital the lesser the chance of a full recovery.

The novel approach is expected to bring better results based on the fact that there is a smaller impact on the patient’s body. This should result in faster recovery


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rates, less time spent at the hospital post operatively, fewer complications such as bleeding, infections and neurological events and an overall higher survival rates.

1.2 Endpoints

Primary:

The primary endpoint is 12-month survival.

Secondary:

The secondary endpoints that I will evaluate are: the time spent intrahospital, sepsis, creatinine levels, renal failures and reoperations.


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2. Presenting the Left Ventricular Device

The following chapter 2.1 gives a background about the historical development of mechanically circulatory support systems. The device that is implanted in this study population is described thereafter with a technological outlook into the up to date development in chapter 2.2. The focus of this study lies on the two different implantation techniques which are described in chapter 2.3.

2.1 History

In 1952, Dr. Dodrill developed the first mechanical heart. The Dodrill GMR (General Motors Research) performed the function of the heart external to the body and provided the possibility of stopping the real heart. (7) With this device, manipulations of the heart became possible. Only one year later, Dr. Gibbon introduced an oxygenator for cardiopulmonary bypass, this marked the beginning of open heart surgery. (8) In December 1967, Dr. Barnard performed the first successful human heart transplantation. (9)

This ground-breaking operation opened up a new era in heart surgery. End-stage heart failure now became treatable through transplanting a healthy donor heart. With advancing medical treatment gained through this early experience transplantation therapy became a viable option for patients previously considered terminal. Shortage of donor hearts however made it necessary to develop other treatment options. It was Dr. Liotta who implanted the first ventricular assist device (VAD) in 1963. This procedure was meant as an acute support option for patients in cardiogenic shock. (10) With the possibility of longterm VAD treatment in mind, the US National Heart Lung and Blood Institute was established in 1964. What followed was rapid development. In 1969, Dr. Cooley was the first to use an artificial heart to bridge time to transplant. (11) His patient being successfully transplanted three days after the initial artificial heart implantation. Dr. de Vries took the next step in 1982 when he performed the first permanent implant of an artificial heart. (12) There was much controversy surrounding the use of total artificial hearts, yet at the same time waiting lists for heart transplantations grew enormously. (13) This and the positive results of previous VAD implants paved the way for continuous and innovative development of ventricular assist devices. There was and still is however a huge discrepancy between donor availability and patients who desperately need a transplant. The mortality rate for patients on the heart transplant waiting list within one year is 30% and the 5-year survival rate of 50% is even worse. (2) In the beginning of artificial heart designs, engineers thought that it was best to build a device that mimicked a real hearts functionality. Therefore pulsatile devices were developed; these contained valves as well as a dilating and contracting part. There were a lot of moving parts, which had to withstand enormous wear and tear forces. These devices had a high rate of material failure and a high rate of thrombus formation. Trying to combat the high likelihood of thrombus necessitated the use of high dose anticoagulant therapy. This led to associated multitude of bleeding events. There has been a lot of controversy about the necessity of a pulse for the human body to function properly. Through a recent RCT the need of a pulse has been evaluated. One


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patient group received the standard pulsatile pump „HeartMate XVE” and the other group received the continuous flow pump „HeartMate II” (both from Thoratec Corp., Pleasanton, CA, USA). (14) The continuous flow pumps have shown significant better survival rates and have therefore replaced the pulsatile pumps and proven that there is no essential need for a pulse. This was a huge breakthrough as continuous flow pumps can be built in smaller dimensions and need only one single moving part, the impeller. Thus the technical failure rate dropped considerably and the smaller size made it possible to implant the pump completely into the body. Only the controller and the batteries have to be worn on the exterior and are connected with the pump through the so-called 'driveline'. This grants a great level of mobility to the patients. The size of early VADs demanded a big thoracic opening, a complete median sternotomy. This high-risk surgery has a huge impact on the patient’s constitution and is bound with many possible complications. Because of the associated risk factors, only a small group of severely ill patients gain access to this treatment. HeartWare recently developed a new VAD, with the product name „HVAD”. This device is even smaller than its precursors and opened the possibility for a new, even less invasive method of implanting the device. A group of surgeons at the MHH developed a novel minimally invasive technique in 2011, in which the HVAD is implanted through an upper hemisternotomy combined with a left sided anterolateral thoracotomy. (4) Treatment with a VAD is still an ultima ratio therapy for patients with end-stage heart failure and insufficient blood circulation, even under optimal medical treatment. As a first step after diagnosing insufficiency of medical treatment, all other surgical options should be considered before implanting a LVAD. (13) A mechanical assist implantation is a high-risk surgical procedure and goes along with great risk of severe complications such as severe hemorrhage, lung embolism, stroke and so forth. The overall bad general state of health (GSH) of the patient group is one part of the problem, the other main concern is the invasiveness of an extended surgical opening on the weak patient. The process of evaluating the best suited treatment for a patient, involves calculating the risks and to counterbalance them with the possible benefits of the treatment. This makes the VAD treatment only suited for severely sick patients. Reducing the risk score would make the treatment available to a greater, healthier population and with this process the overall outcome of VAD treatment could enormously improve.

2.2 Device

2.2.1 The HVAD® Pump HeartWare is a global medical device company, producing Ventricle Assisting Devices (VAD) for Mechanical Circulatory Support (MCS). (15) In 2007, human trials started at the MHH with the HVAD. The HVAD is a centrifugal pump, which is constructed to provide full output for patients with end-stage heart failure. Such patients have a heavily reduced cardiac ejection fraction, leading to insufficient circulation. The design of the device is such that it is implanted into the pericardial space.

Figure 1: HVAD in Hand

Courtesy of Heartware,

Inc, Miami Lakes, FL,

USA. (15)


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The main part of the HVAD, the pump itself, is inserted and sutured to the apex of the heart at the left ventricle. This position brings the suction cannula into the right angle, facing the mitral valve (Fig. 3). The HVAD now draws the arterial blood out of the left ventricle into a flexible pipe, which is connected to the ascending part of the aorta (Fig. 2). The blood flow is then no longer depending on the aortic valve. Another, less frequently used option is the connection to the descending part of the aorta. One of the novel features of this device is the floating impeller. Importantly there is no rigid mechanical contact between the impeller and the housing. According to the manufacturer, this greatly improves the coagulation situation. Earlier devices always had a contact point, even if very small, there always arises friction and heat production. With friction and rising temperature there is high chance of coagulation. The novel impeller is held in a so-called 'magnetic cage', which fixates the impeller without any actual contact. The small space between the impeller and the housing needs lubricant in order to stay sufficiently cooled, this lubrication comes from the patient’s own blood. The space

between impeller and housing is too small for the blood cells to slide past but large enough for blood plasma. By the rotation of the impeller, the blood gets drawn into the device and pushed into the aorta. With this movement the blood plasma circulates around the impeller and enables a smooth rotation as well as the necessary cooling. This can strongly reduce the risk of thrombosis. The impeller

needs no further cooling or lubricant as the patient's plasma is sufficiently adequate. In order to have met the cooling demand, the required minimum speed is 2500 rotations per minute (rpm). Running slower than this limit would result in insufficient suction of the pump, temperate rise and thus a higher risk of blood coagulation and thrombosis. If necessary it is possible to completely take over the patient’s heart function up to a maximum flow of 10 l/m. after implanting the LVAD the heart is relieved of much stress. The LVAD takes over the necessary workload and in many patients the aortic valve becomes effectively permanently closed. This can be seen with echocardiography. The effect of this is that, quite often after several months a degree of recovery in the cardiac tissue is seen. In January 2009 HeartWare received the European Commercial approval for the HVAD, but it was not before November 2012 that they obtained the most recent bridge-to-transplant (BTT) approval by the U.S. Food and Drug Administration (FDA). (1) 2.2.2 Technology Pipeline Development of the LVADs is constantly improving, HeartWare is currently working on an improved not yet released version the MVAD® (Fig. 4), with human trials to commence at the end of this year. The dimensions of this pump are very promising. It is much smaller and therefore enables again a smaller implanting

Figure 2: Anatomical

position Courtesy

of HeartWare, Inc, Miami

Lakes, FL, USA. (15)

Figure 3: HVAD Blood flow and positioning on patient (16)


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approach. I can say, the smaller the impact of the surgery for the patients the better the expected outcome. This observation has already been proven by other studies in other fields of surgery and the trend can be seen in my results. The MVAD is another step towards better results. Not only the dimensions have decreased but the key focus on development has been to produce a fully implantable device. All modern LVAD´s use a driveline, which is tunneled through the skin and connected to a controller and the batteries. Because of the driveline there always has been a gap in the lower stomach region, providing a route for infection. Full implantation and therefore no artificial opening of the abdomen should be a massive step in improving the outcome of this treatment. There is a novel technique, the MVAD, utilizing the novel technology of transcutaneous energy transfer (TET). This technology enables the MVAD to be fully implantable. The controller and the battery pack will be implanted. The batteries will be periodically recharged using inductive coupling across the skin. (1) With this technique the patients get a whole new degree of freedom. It will be possible to take a swim as almost everything a healthy person can do. This novel technology is expected to be available in just a few months and is awaited to have a major impact on LVAD treatment. The dimensions of this device are even smaller then the HVAD which creates an even higher urge of a minimally invasive technique to implant the MVAD in the future. To compare the HVAD with the MVAD will be a greatly interesting study for future investigations. 2.3 Surgical Technique

2.3.1 Conventional HVAD implantation

“The patient in the supine position is prepped and draped in the usual sterile fashion. If the patient does not have a need for access to the lower extremities, then a Bair Hugger (Arizant Healthcare Inc, Eden Prairie, MN) is used to help maintain normothermia. A median sternotomy is performed, and the pericardium is opened as far to the left as possible. This makes a pericardial flap that can be placed over the right ventricle at the completion of the procedure. The heart and great vessels are inspected for any abnormalities and the best location for the outflow graft. Before heparinization, the driveline exit site should be prepared, and the driveline should be tunneled beneath the rectus muscle. The driveline is routinely brought out the left upper quadrant. It should be several centimeters below the costal margin and above the patient’s belt line. I no longer leave any polyester outside the skin and prefer to leave the end of the polyester-covered portion of the driveline completely in the subcutaneous tissue about 1 cm from the skin edge. The pump, outflow graft, and driveline are then wrapped in bacitracin-soaked laparotomy pads. The patient is then systemically heparinized. Cardiopulmonary bypass cannulation is performed with a 2-stage venous cannula

Figure 4: Future device MVAD (left) and the HVAD

Courtesy of Heartware, Inc, Miami Lakes, FL, USA. (1)


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and an arterial cannula in the proximal aortic arch. The pump prime is removed by using the retrograde autologous prime technique. The patient is then placed on cardiopulmonary bypass, and the procedure is performed on the decompressed beating heart. The location of the inflow cannula is critical to longterm pump performance. Ideally, it should be parallel to the septum and pointing toward the mitral valve. To consistently achieve this orientation, the sewing ring is attached to the epicardial surface on the distal LV anterior wall approximately 2 cm lateral to the left anterior descending coronary artery. Twelve pledgeted sutures (2-0 Ethibond; Ethicon, New Brunswick, NJ) are placed deep in the myocardium and then through the Dacron portion of the sewing ring (Fig. 5A). Once seated and all sutures tied, a cruciform incision is made in the LV. The LV punch is inserted through the incision, and a full thickness circular left ventriculotomy is executed.

The LV cavity should be inspected for thrombi and crossing chordae tendineae. (16) The inflow cannula is inserted into the LV opening, and the pump is rotated so that the outflow graft and pump outlet are directed toward the right thorax. The inflow cannula and pump are secured in place by tightening an integrated screw in the C-clamp titanium ring (Fig. 5B). The outflow graft is distended and trimmed for proper length. The distal anastomosis is completed end-to-side by using a 4-0 polypropylene suture to the greater curvature of the ascending aorta (Fig. 6).

De-Airing and Weaning from Bypass De-airing of the LV, pump, and outflow graft is confirmed by TEE before beginning HVAD support. Before coming off bypass, a needle is inserted in the outflow graft for additional de-airing. The HVAD is started at 1800 rpm, and the clamp is removed from the outflow graft. Once cardiopulmonary bypass flow is _500

Figure 5: (A) Artist's illustration of placement of the sewing ring on the LV surface (permission from HeartWare International, Inc). (B) Left ventriculotomy within the sewing ring that allows for inspection of the

LV cavity. (16)

Figure 6: Outflow graft residing in the pericardial space

so that it will reduce risk of traumatic injury on re-entry.

(16)


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mL/min, the HVAD speed is increased, cardiopulmonary bypass is terminated, and the needle is removed from the outflow graft. The bypass cannulas are removed, and the pump and graft are checked for kinking or misalignment. The pericardial flap is placed over the right ventricle free wall and secured with several interrupted sutures. Mediastinal drainage tubes are inserted, and the chest is closed (Fig. 7).” (16,17)

2.3.2 Minimally invasive HVAD Implantation “The minimally invasive HVAD (HeartWare Inc., USA) implantation approach was developed by three groups including Hanover, London-Harefield and Vancouver. The combination of an upper hemisternotomy with a left-sided anterolateral thoracotomy was introduced by Schmitto et al.. Firstly the patient is put on cardiopulmonary bypass using venous cannulation into the right femoral vein and performance of the arterial cannulation into the ascending aorta via upper hemi-sternotomy. By avoiding a full sternotomy, the pericardium remains mainly closed,

preserving the natural right ventricular delimitations and thereby avoiding right ventricular dilatation during LVAD-onset. Thus right ventricular function remains passively sustained. In a second step an anterolateral thoracotomy is performed and an epicardial HVAD-sewing-ring implanted on the left ventricular apex. Then, the HVAD-pump is placed through the sewing ring into the left ventricular apex. The outflow graft is tunneled through the pericardium and afterwards anastomosed end-to-side to the ascending aorta through the upper hemi-sternotomy. The driveline is firstly placed in the sheath of the rectus muscle in umbilical direction and then subcutaneously to the right or left upper quadrant. This approach enlarges the subcutaneous driveline course decreasing infection rates. After de-airing of the device, the pump is started in situ. Pump speed must be gradually

Figure 7: Chest radiograph of the HVAD pump totally

contained within the thoracic cavity. (16)

Figure 8: (A) Upper hemisternotomy to perform arterial cannulation to the ascending aorta as well as for implantation of the outflow cannula of the centrifugal pump. (B) In situ placement of the HeartWare ventricular assist device pump through the anterolateral thoracotomy. (4)

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increased during weaning from the ECC. Mean pump flow of 5 ± 0.5 l is usually achieved with left pump running at 3000 ± 200 rpm. While this procedure is mainly performed on-pump, Cheung et al. successfully applied it without use of heart-lung machine. Following the idea of fully avoiding sternotomy, Popov et al. applied a combination of bilateral anterior thoracotomies for the HVAD.” (4)


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3. Material and methods

The study settings and the statistical analysis are further described in this chapter.

3.1 Study Design

I performed a single center clinical retrospective outcome analysis comparing the outcome of the novel minimally invasive implantation technique of the HVAD versus the conventional surgical approach. This study involved no direct patient contact and no additional examination has been done. All information evaluated had been previously gathered and stored in the MHH database “Alida”.

3.2 Study Population

In this analysis, 66 patients with advanced heart failure were selected, all of which have been treated at the MHH with a HVAD between 29th of January 2010 till 21st of March 2012. This time frame grants a minimum postoperative follow-up of 12 month. Patient selection was carried out respecting the inclusion/exclusion criteria listed in Table1.

All patient information used has been collected from the “Alida“ database, a hospital wide digital patient information network from the MHH. The selected patients have been anonymized and there was no influence through this study on the patient’s treatment. The chosen population has been divided into two groups. Group A (conventional) with 37 patients who received the HVAD through the full median sternotomy and 29 people in group B (minimally invasive), who received the novel implantation procedure. Both groups have been treated with the HVAD from HeartWare.

To minimize the confounders of this study, the HVAD has been chosen to evaluate the new implantation technique. This device is implanted all over the world, using the conventional surgical approach, the full sternotomy. This exact same device is also implanted using the novel minimally invasive technique at only a few specialized heart centers such as the MHH. This fact eliminates all device depending complications, which are exactly the same in both groups. And therefore it becomes possible to compare the surgical techniques separately.

3.2.1 Statistical Analysis

Table 1: Inclusion & Exclusion criteria

Inclusion criteria

Inclusion criteria

Registration in the ALIDA information base of the MHH (Medical School Hanover)

18 years or older

HVAD treatment between 29.01.2010 and 21.03.2012

End-stage heart failure

HVAD Implantation through upper hemisternotomy combined with anterolateral thoracotomy or conventional full median sternotomy

Exclusion criteria

Implantation through other surgical approaches

Younger than 18 years

Patients operated in hospitals other than the MHH

Chronic infections preoperative


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The statistical analysis was performed with SPSS 20.0 (IBM SPSS Statistisics, IBM Corp., Armonyk NY, USA). I used the Student’s t-test, Cross-Tabulation with Pearson’s Chi-Square test, matched-paired analysis and the non-parametric Kaplan Meier survival and Mann-Whitney U tests for statistical evaluation. Differences were considered significant at p ≤ 0.05. All results are presented as mean ± standard deviation (SD).


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__________________________________________________

* For all tables applies: Plus-Minus values are means ± SD

4. Results

There are 66 patients with advanced heart failure included in my study. 55 men and 11 women have met the inclusion/exclusion criteria and have been included in the study. The mean age of the selected population was 52. All of the candidates had heart failure of various etiology: 46% dilatative cardiomyopathy (DCM):38% ischemic cardiomyopathy (ICM). In 16% of the cases the cardiomyopathy has not been further differentiated. 37 patients underwent conventional HVAD implantation and 29 patients were treated with the novel approach. The male predominance in both groups was equally stated with 83-84%. In Tables 2-4, all preoperative patient parameters are presented in order to grant a comparable evaluation of the GSH of all patients. Table 2 shows the preoperative baseline characteristics. Evaluating the data there are slight differences but no p-value shows a statistical significance. To further evaluate the preoperative state of the two groups and to prove their equality I have collected additional data.

Subgroup

Total

Mean ± SD

Group A

Conventional

(N=37)

Mean ± SD

Group B

Minimally Invasive

(N=29)

Mean ± SD

P

Age - yr

Mean 52 ± 12 52 ± 12 52 ± 13 0,89

Median (range) 53 (19-75) 54 (20-75) 53 (19-73) 0,62

Male (no. (%)) 55 (83) 31 (84) 24 (83) 1.00

Female (no. (%)) 11 (17) 6 (16) 5 (17) 1,00

DCM (no. (%)) 30 (46) 19 (51) 11 (39) 0,45

ICM (no. (%)) 25 (38) 12 (32) 13 (46) 0,31

eGFR (no. (%))

<20 ml/min/1.73m2 3 (5) 2 (5) 1 (3) 1,00

20-60 ml/min/1.73m2 28 (42) 18 (49) 10 (35) 0,32

>60 ml/min/1.73m2 35 (53) 17 (46) 18 (62) 0,22

Serum Sodium mmol/l 137 ± 5 137 ± 6 136 ± 4 0.12

Serum Creatinine mg/dl 127 ± 101 133 ± 115 118 ± 81 0.55

Serum Billirubin mg/dl 36 ± 57 41 ± 70 27 ± 18 0,27

BPM mmHg 75 ± 9 76 ± 9 73 ± 10 0.20

Hb mmol/l 11 ± 2 11 ± 2 12 ± 2 0,24

BMI kg/m2 27 ± 5 27 ± 5 27 ± 5 0,55

BSA m2 2 ± 0,2 2 ± 0,2 2 ± 0,2 0,88

Days of artificial ventilation 3 ± 14 0,5 ± 1.5 5 ± 21 0,27

INTERMACS 4 ± 2 4 ± 1,8 4 ± 2 0,63

SHF Score

3 ± 2 3 ± 2 4 ± 2 0,45

Table 2: Baseline characteristics – preoperative *


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Table 3: Co-Morbidities preoperative

The Co-Morbidities in Table 3 provide further information about the condition of the patients before receiving the HVAD. There was a small number of 4 patients who had diabetes and were being treated with insulin in group B, on the contrary no one in group A is diabetic. This is the only statistically significant difference between both groups shown in this Table. Even though not statistically significant there are a few differences visible. 24% of the patients in group A had a moderate pulmonary hypertension and 11% had a severe pulmonary hypertension. In group B on the contrary, 52% enrolled with moderate pulmonary hypertension and 31% had severe pulmonary hypertension. This trend is supported throughout the values of patients with CCSIV (Canadian cardiovascular society, CCS IV= Inability to perform any activity without angina or angina at rest, i.e., severe limitation) and the higher need of catecholamines preoperative in group B. On the other hand there are a few categories in which patients in group A had a worse state than group B. Hyperlipidemia and the times of reoperation describe a slightly better constitution of the patients in group B. The general constitution of the heart function can be measured through echocardiography and right heart catheter (Table 3).

Subgroup

Group A

Conventional (N= 37)

no. (%)

Group B

Minimally Invasive (N=29)

no. (%)

p

Diabetes on Insulin 0 (0) 4 (14) 0,03

Pulmonary Hypertension 13 (35) 15 (52) 0,21

Moderate 9 (24) 9 (31) 0,59

Severe 4 (11) 6 (21) 0,32

Chronic Lung disease 3 (8) 2 (7) 1,00

Active Endocarditis 0 (0) 0 (0) -

Renal Failure 17 (46) 13 (45) 1,00

Hyperlipidemia 9 (24) 4 (14) 0,37

Tumor 1 (3) 3 (10) 0,31

Re-Operation 19 (51) 12 (41) 0,46

Critical state 14 (39) 10 (36) 1,00

Recent MI 5 (14) 4 (14) 1,00

In need of catecholamine 11 (31) 11 (41) 0,43

CCS IV 1 (3) 2 (7) 0,57

Mechanical assist

IABP 5 (14) 3 (11) 1,00

ECMO 9 (25) 5 (19) 0,76

IABP&ECMO 5 (14) 2 (7) 0,69

In general, there is no statistically significant difference evident. Nevertheless there are differences between group A and B. The average size of the left ventricular end-diastolic diameter for example is 5 mm smaller in group B than in group A. The same is to be seen by the left ventricle's end-systolic diameter (LVEDD). Group B shows a 1 mm wider diameter then group A. The different pressures can be very revealing on the heart condition. The mean pressure of the right atrium was 4 mmHg less in group B. The same trend can be seen at the


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aortic pressure. The mean transpulmonary gradient manifests a difference in pressure of 8mmHg in group A compared to 15 mmHg in group B. All of the available preoperative data demonstrate almost no statistically significant differences. Although there where slight fluctuations between the groups and there is no statistically significant proof that either of the two groups arise from different populations. All available preoperative data showed no important differences, however there is one parameter statistically significant. There were 4 patients who had insulin

treated diabetes in group B and none in group A. Although retrospective, this supports the assumption that both groups represent in fact an identical population. The postoperative baseline characteristics are stated in Table 5 presenting the results of the postoperative examination. All of these values were measured within 10 days after implantation. None of the listed values demonstrate statistically a significant difference between the groups, nevertheless there are still certain obvious discrepancies to be seen. The mean Hb in group A is (to a minor degree) higher than in group B. The liver enzymes are clearly reduced in group B. Also there are less amounts of the liver enzymes AST,ALT and GLDH (21,13,9 IU/l) found in the patients' serum in group B. Not statistically significant but certainly divergent is the amount of thrombocites. Group B presents a mean thrombocyte count of 160x109/l compared to 133 x109/l in group A. The mean amount of C reactive protein (CRP) registered is 146mg/l in group B which is 8mg less of the value of CRP found in group A. The same trend is witnessed when looking at the mean amount of fetal hemoglobin. Group A presents 108mg/dl and group B just 96mg/dl. There is no statistical significant difference however between the two groups postoperatively.

Subgroup

Group A

Conventional (N=37)

mean ± SD

Group B

Minimally Invasive (N=29)

mean ± SD

p

RA Mean (mmHg) 18 ± 10 14 ± 8 0,29

PA Systole (mmHg) 54 ± 24 55 ± 18 0,92

PA Diastole (mmHg) 27 ± 11 29 ± 10 0,58

PA Mean (mmHg) 38 ± 15 38 ± 12 1,00

PCWP (mmHg) 28 ± 10 26 ± 12 0,53

TPG (mmHg) 8 ± 9 15 ± 11 0,11

Aorta (mmHg) 87 ± 15 84 ± 18 0,72

SVR (dyn·s/cm) 1600 ± 947 1620 ± 508 0,95

PVR (dyn·s/cm) 333 ± 197 258 ± 112 0,26

FICK HZV 3,72 ± 1,2 3,44 ± 1,2 0,43

Subgroup

Group A


mean ± SD

Group B

Minimal-invasive (N= 29)

mean ± SD

p

Serum Sodium (mmol/l) 138 ± 5 137 ± 4 0,30

Serum Potassium (mmol/l) 5 ± 0,4 5 ± 0,5 0,86

Serum Creatinine (mmol/l) 125 ± 66 127 ± 93 0,90

Hemoglobin (mmol/l) 12 ± 5 11 ± 1 0,30

Serum AST (IU/l) 129 ± 145 108 ± 104 0,50

Serum ALT (IU/l) 52 ± 68 39 ± 43 0,37

Serum GLDH (IU/l) 28 ± 113 19 ± 59 0,71

Leucocytes (109/L) 13 ± 5 12 ± 3 0,26

Thrombocytes (/ml) 133 ± 59 160 ± 69 0,10

Urea (mmol/l) 11 ± 7 9 ± 6 0,20

Quick (%) 61 ± 15 59 ± 15 0,66

INR (sec.) 1 ± 0,3 1 ± 0,4 0,86

CRP 154 ± 86 146 ± 87 0,70

eGFR

< 20 ml/min/1.73m2 (n/%) 1 (3) 4 (16) 0,15

20-60 ml/min/1.73m2 (n/%) 14 (41) 5 (20) 0,10

> 60 ml/min/1.73m2 (n/%) 18 (53) 17 (68) 0,29

LVEF (%) 19 ± 3 19 ± 4 0,78

LVEED (mm) 53 ± 16 59 ± 10 0,10

LVEF 1 year postoperative (%) 25 ± 12 26 ± 5 0,69

LVEDD (mm) 56 ± 17 56 ± 9 0,92

Blood Transfusion total 30 ± 30 21 ± 31 0,27

LDH 1 year postoperative (IU/l) 259 ± 85 249 ± 62 0,68

Fetal Hemoglobin (g/dl) 108 ± 74 96 ± 68 0,61

FICK Cardiac index

1,95 ± 0,7 1,67 ± 0,7 0,82

LVEF (%) 18 ± 9 19 ± 6 0,64

LA (mm) 51 ± 14 51 ± 11 0,89

LVEDD (mm) 72 ± 11 67 ± 8 0,07

LVESD (mm) 61 ± 10 62 ± 8 0,91

Table 4: Echo & Catheter - preoperative


19

Subgroup

Group A


Group B

Minimal-invasive (N= 29)

p

Serum Sodium (mmol/l) 138 ± 5 137 ± 4 0,30

Serum Potassium (mmol/l) 5 ± 0,4 5 ± 0,5 0,86

Serum Creatinine (mmol/l) 125 ± 66 127 ± 93 0,90

Hemoglobin (mmol/l) 12 ± 5 11 ± 1 0,30

Serum AST (IU/l) 129 ± 145 108 ± 104 0,50

Serum ALT (IU/l) 52 ± 68 39 ± 43 0,37

Serum GLDH (IU/l) 28 ± 113 19 ± 59 0,71

Leucocytes (109/L) 13 ± 5 12 ± 3 0,26

Thrombocytes (/ml) 133 ± 59 160 ± 69 0,10

Urea (mmol/l) 11 ± 7 9 ± 6 0,20

Quick (%) 61 ± 15 59 ± 15 0,66

INR (sec.) 1 ± 0,3 1 ± 0,4 0,86

CRP (mg/l) 154 ± 86 146 ± 87 0,70

eGFR

<20 ml/min/1.73m2 (n/%)

1(3) 4(16) 0,15

20-60 ml/min/1.73m2 (n/%)

14(41) 5(20) 0,10

>60 ml/min/1.73m2 (n/%)

18(53) 17(68) 0,29

LVEF (%) 19 ± 3 19 ± 4 0,78

LVEED (mm) 53 ± 16 59 ± 10 0,10

Blood Transfusion total 30 ± 30 21 ± 31 0,27

Fetal Hemoglobin (g/dl) 108 ± 74 96 ± 68 0,61

The condition of the patients during their intrahospital stay is listed in Table 6. Even though not significant there is a difference in the 30 day survival between the groups. In group A, 84% of the patients survived the first 30 days postoperative while group B this was 93%. All major complications stated in this table have been grouped and presented as total complications. The mean rate of complications in group A is 2 and in group B is 0,8. That is, group B has 60% less complications in general. This difference is represented through a p value of 0,05 and is therefore statistically significant. Bleeding occurrences which required surgical interference happened less frequently in group B (3%) than in group A (14%). The same can be said about the quantity of the right heart failures. In group A, right heart failure occurred more often (22%) than in group B (10%). The characteristics prolonged respirator time and pump replacements while LVAD thrombosis show at least 50% fewer events in group B. There are even bigger differences to be seen when comparing the events of sepsis between the groups. Group A includes 7 (19%) cases of sepsis while in group B only one patient (3%) is afflicted with sepsis. This difference presents a p-value of 0,07 and therefore is not yet significant. The results after one year postoperative are stated in Table 7. In the conventionally treated group there were 28 out of 37 (76%) patients who survived 12 months postoperative. Conversely in the group treated with the novel approach, 25 patients out of 29 (86%) were still alive after this time. While the p value of 0,28, is

Table 5: Postoperative Baseline


20

Table 6: Adverse Events - Intra-Hospital

not statistically significant, I still contend that 76% vs. 86% shows a definitive trend at the very least.

Subgroup

Group A

Conventional (N=37)

(29 patient-yr)

Group B

Minimal-Invasive (N=29)

(25 patient-yr)

p

mean ± SD no. of Events/Patient-Yr

mean ± SD no. of Events/Patient-Yr

Total Complications (n) 2,2 ± 2,2 (81) 2,79 1,1 ± 1,3 (37) 1,48 0,02

no. (%) no. (%)

30 day survival 31 (84) 1,07 27 (93) 1,08 0,45

Bleeding requiring surgery 5 (14) 0,17 1 (3) 0,04 0,22

Right heart failure 8 (22) 0,28 3 (10) 0,12 0,32

Managed with Inotropes 8 (22) 0,28 3 (10) 0,12 0,32

Managed with ECMO 2 (5) 0,07 0 (0) 0,00 0,50

Managed with RVAD 2 (5) 0,07 0 (0) 0,00 0,50

Infection 2 (5) 0,07 1 (3) 0,04 1,00

LVAD related Infection 1 (3) 0,05 1 (3) 0,04 1,00

Non-LVAD related Infection 2 (5) 0,07 0 (0) 0,00 0,50

Renal Failure 5 (14) 0,17 5 (17) 0,20 0,74

Hepatic dysfunction 1 (3) 0,05 0 (0) 0,00 1,00

Sepsis 7 (19) 0,24 1 (3) 0,04 0,07

Technical Complications 1 (3) 0,05 0 (0) 0,00 1,00

Bleeding Events 12 (35) 0,41 5 (21) 0,20 0,26

Prolonged respirator time 8 (22) 0,28 3 (10) 0,12 0,32

Pump replacement 5 (14) 0,17 2 (7) 0,08 0,45

HIT 0 (0) 0,00 2 (7) 0,08 0,17

Neurologic events 2 (5) 0,07 0 (0) 0,00 0,50

LVAD Thrombosis 1 (3) 0,05 2 (7) 0,08 0,58

The complications that have occurred during the first year after implantation have been grouped and stated in total complications. Group A had 88 complications (mean =2) while Group B had 35 events (mean = 1) showing a lower occurrence rate of complications. Significantly fewer complications occurred in Group B as reflected by the p value of 0,001.The infection rate of driveline infection as well as sternal infections also occurred less frequently in group B. Further, the same can also be stated about neurologic events. In group A there are 4 cases of neurologic events whereas group B had none. LVAD thrombosis, pump exchange, right heart failure, bleeding requiring surgery and prolonged respiratory time altogether show at least 50% fewer events in group B then in group A. Figure 9 shows the Kaplan Meier survival curve of group A (blue) and group B (green). The mortality rate of both groups divides within the first few days after implantation already. Group A has a lower percentage of survival throughout the entire table ending in a 12 month survival rate of 76%. Group B shows a 12 month survival rate of 86%. This table demonstrates the minimally invasive implantation technique granting a higher rate of survival the conventional technique.


21

Subgroup

Group A

Conventional (N=37)

(29 patient-yr)

Group B

Minimal-Invasive (N=29)

(25 patient-yr)

p

no. (%) no. of Events/Patient-

Yr

no. (%) no. of Events/Patient-

Yr

12 Month Survival 28 (76) 0,97 25 (86) 1,00 0,28

Total Complications (n) 2 ± 2 (88) 3,03 1 ± 1(35) 1,40 0,001

Driveline Infection 13 (35) 0,45 4 (14) 0,16 0,09

Neurologic Events 4 (11) 0,14 0 (0) 0,00 0,13

Hepatic Dysfunction 1 (3) 0,05 0 (0) 0,00 1,00

LVAD Thrombus 5 (14) 0,17 2 (7) 0,08 0,45

Pump Exchange 5 (14) 0,17 2 (7) 0,08 0,69

Right Heart Failure (RHF) 7 (19) 0,24 2 (7) 0,08 0,28

Managed with RVAD 2 (5) 0,07 0 (0) 0,00 0,50

RHF managed with ECMO 5 (15) 0,17 0 (0) 0,00 0,06

Sternal Wound Iinfection 4 (11) 0,14 1 (3) 0,04 0,38

Long or very high need of catecholamine

18 (50) 0,62 8 (31) 0,32 0,19

Bleeding Requiring Surgery 5 (16) 0,17 1 (4) 0,04 0,21

Renal failure 5 (14) 0,17 5 (18) 0,20 0,73

Re Operation 21 (58) 0,72 14 (70) 0,56 0,57

Re-Hospitalization 18 (49) 0,62 14 (52) 0,56 1,00

LVAD related Re-Hospitalization

10 (27) 0,35 6 (21) 0,24 0,58

Prolonged Respirator Time 8 (22) 0,28 3 (11) 0,12 0,32

Technical failure 2 (6) 0,07 0 (0) 0,00 0,50

ICU Stay (days) 13 ± 15 12 ± 15 0,87

Total Intrahospital Stay (days) 32 ± 23 39 ± 29 0,30

The 12 month survival rates of both groups compared to each other does not yet present a statistically significant difference. In order to be able to include more patients we looked at a shorter period of time, 10 months instead of 12. Through this it became possible to include 13 more patients in total. 12 of which underwent the novel minimally invasive implantation treatment and one patient that received the conventional method. This distribution displays the ratio of the two techniques being used. The results are displayed in figure 10 and table 8. The 10-months survival rate of the 72 patients shows a significant difference between the groups. The survival curves of both groups can be seen in figure 10 with the blue line being group A and green being group B. The p value of 0,043 states that group B has a statistically higher survival rate than group A. This outcome supports the earlier stated trend of group B providing a higher survival rate then group A (Fig. 9). Also stated in figure 10 are the survival rates found in two published papers from Slaughter et al. (brown) and Rose et al.(black). The survival curve presented from Slaughter et al. is based on patients treated with a continuous flow LVAD (HeartMate II). All of these patients have been treated with the conventional implantation approach. Rose et al. show the survival rate of patients with end stage heart failure who only received the best medical treatment available. The

Table 7: Adverse Events - 1-Year

postoperative


22

curves speak for themselves presenting worse outcomes then the data found through this study.

Figure 9: Kaplan Meier survival curve.12 month follow up. Group A (n=37) Group B (n=29)


23

Total N

N of Events Censored

N Percent

Group A 34 12 22 64,7%

Group B 38 5 33 86,8%

Total 72 17 55 76,4%

Figure 10: Kaplan Meier survival curve. 72 Patients have been included and divided into 34 in the conventional

group and 38 in the minimally invasive group. Patients who have been explanted and or transplanted have been

excluded of the evaluation in order to grant a follow up of at least 10-month. (16,18)

Table 8: Extended Kaplan Meier Results

postoperative


24

5. Discussion

This retrospective study has been focused on the possible beneficial effects of the minimally invasive surgical procedure compared to the conventional approach. The most important difference I have found is that there is a difference in the postoperative survival in favor of the novel technique. Furthermore there are positive trends crystallizing comparing the amount of cases which showed postoperative infection, neurologic events and the occurrence of right heart failure. Especially the numbers of patients who needed ECMO treatment have been clearly smaller. Even statistically significant is the difference between the two groups comparing the overall postoperative complication rate. These findings stand in line with the already published results (4,18-22) Even though there are a few slight differences in the technique the surgeons used in the mentioned papers, all of them have chosen a less invasive technique over the complete median sternotomy with positive results. There is still the need of a multicenter evaluation of the novel technique with a broader population in order to make the minimally invasive approach the gold standard but the results of the already published cases are very promising. The hart center at the MHH is a highly specialized institute. This factor is important to keep in mind for several reasons. The surgeons in this hospital have a high number of end-stage heart failure patients. The continuously growing population of LVAD patients led to steady improvements in their surgical skill and experience. The outcome of the LVAD implantation still is very much surgeon dependent. The implantation of LVADs is considered a high-risk surgery and therefore this treatment is suggested to be done only at specialized heart centers like the MHH. The majority of patients develops end-stage heart failure over a longer period of time and is treated at facilities in their neighborhood. It is not until all other treatment options have failed that an implantation of an LVAD becomes the only available sufficient solution. In most cases, years of treatment and examinations have (passed prior to the operation. The moment of implantation is mostly not to be predicted to an exact date but patients get implanted on short notice and come from all over the world, often arriving in bad GSH. That is why in some cases, it is not possible to do time-consuming preoperative evaluation and only the absolutely necessary examinations are done and documented. Sometimes there is insufficient communication possible between the surgeon and the attending doctor. This is the reason why there are some values missing in the calculations. Postoperatively, a lot of patients are cared for by prior medical professional in their surrounding area. The normal follow up is to be done through artificial-heart coordinators. This is a specialized team of medical care personnel who stay in frequent contact with the patients. They have to constantly evaluate the postoperative condition and the need of interference for the LVAD-Patients. Unfortunately, not all patients come back to the MHH for continuous follow-up, there are a lot of patients seeking treatment from foreign countries who do not have the option to come back for control appointments. Thus the medical data of these patients is somehow limited and the best possible care is not granted if not followed by a specialist. The HVAD has been introduced at the MHH in 2007 in context of a clinical trial. It was not until January 2009 that the HVAD got the European Commercial approval, allowing implantations in specialized heart centers all over Europe. By that time the surgeons at the MHH already had 2 years


25

of experience with the HVAD ahead of the other European surgeons. In 2011 they developed the novel minimally invasive implantation technique. (4) Overall, the situation at the MHH makes it possible to compare the two different approaches without major differences in the evaluated population. The device is the same and the possible complications are very much similar. Different LVAD´s from different manufactures would have involved individual possible technical and medical complications. In order to only compare the surgical techniques alone, it is of great importance to have the same device and the same population of patients. Additionally, the patients in both groups have been treated by the same personnel. Not only the surgeons were the same but also the other healthcare providers who are of great importance to the outcome of the patient treatment were the same in both groups. This study is the first approach of comparing the recently developed novel minimized technique with the standard full sternotomy. The selected population includes only 66 patients in total with only 37 (group A) vs. 29 (group B), making it difficult to receive statistical significances. Since the novel implantation technique has been developed only 2 years ago more time is necessary in order to include a greater population. At this moment it is possible to crystallize interesting trends that still need additional evaluation. The most important of which is the survival. To visualize the 12-month survival I have used the Kaplan Meier curve. As seen in figure 9 and Table 7 there are 28 out of 37 patients who have survived the first 12 month after implantation in group A and 25 out of 29 in group B. This comes down to a 12-month survival rate 76 % vs. 86%. This is a 10% difference, which is not yet statistically significant. As can be seen in the Kaplan Meier curve the survival rate of the two groups diverge already within the first days after implantation. Because the survival rate of group B shows better results after a few days already there is a high possibility that the difference is created through the different surgical approach. Furthermore there are other important differences in the postoperative results of both groups, even though not yet statistically proven. In the postoperative baseline (Tab. 5) there is stated that group B needed a mean of 21 blood transfusions vs. a mean of 30 transfusions in group A. This can be explained by the smaller incisions and the lower impact on the patient’s body. That makes a total mean difference of 30% between the groups. If the selected group had been greater, this result would possibly even have been statistically significant. The thrombocyte count supports the statement that there was less bleeding in group B. In Table 7, it can be seen that there is just one (4%) patient in group B who needed surgical aid because of postoperative bleeding compared to 5 (16%) patients in group A. This again is likely to be a result of the smaller incisions. The C-reactive protein count (Tab. 5) is relatively high in both groups, which is not unusual within the first days after such a major operation procedure. Nevertheless group B has a mean of 8mg/l less CRP compared to group A. This signals a lower inflammation rate in the minimally invasive group. The most obvious parameter to evaluate the efficacy of the heart is the left ventricle ejection fraction (LVEF). The LVEF describes how much of the blood volume gets ejected out of the left ventricle within one contraction cycle of the heart. A normal ejection fraction of the left ventricle varies between 55% and 70% of the total left ventricle volume. (3) The selected patients with advanced heart failure had a mean LVEF of 18% (group A) and 19% (group B) preoperatively. The


26

preoperative left ventricle ejection fraction being a good predictor of insufficient circulation is of no further use after implantation. However the postoperative ejection fraction can possibly rise again. It is possible that the heart function gets restored through relive of the workload through the pump. To monitor the pulsatility of the heart of cores an echocardiography can be done but also the Pulsatility Index (PI) measured and registered through the Pump and its controller gives an impression on the real heart function. LVADs have been developed to function as bridge to transplant (BTT) in the first place. It was meant to keep the patients alive until one of the rare transplant organs becomes available. The success of the LVAD treatment has overcome all expectations and now might even be a bridge to recovery as stated by C. Wood et al. (23). The possible recovery of the heart through taking over its function for a while demands postoperative evaluations of the heart. In case of recovery it is possible to explant the HVAD. Preoperatively, I have evaluated both groups in detail. There are a lot of predictors of heart failure and classifications to evaluate the degree of limitations. One of these categorization systems of heart failure was developed by the New York Heart Association and is called the NYHA-Score. With a NYHA score of IV the patients have severe limitations, experience symptoms even while being at rest and are mostly bedbound patients. (24) In the analyzed population, there were 15 patients with NYHA IV in the conventional group and 13 patients in the minimally invasive group preoperatively (Fig.11). The difference does not yet show a statistically significance but as can be seen in figure 6 the postoperative values show a clear trend. 18 patients in group B vs. 16 patients in group A had a NYHA score of II. Also there is one patient in group A which is still scoring a III-IV after implantation. Again there is no statistically significant difference yet but looking at the numbers it becomes clear that there is a slightly better outcome for the minimally invasive group. Conventionally operated patients dominate the scores of 2-3 and 3. Unfortunately the small total amount of patients makes it difficult to provide a statistically significant difference. Never the less it becomes clear that there is a trend of the minimally invasive group scoring lower on the NYHA classification then the conventional group.

Figure 11: NYHA Score 1-year Postoperative


27

Additional creatinine levels have been found to be an independent predictor of ischemic heart failure. (25) Normal values of creatinine are 0,6 to 1,2mg/dl in an adult male and 0,5 to 1,1mg/dl in adult females. Both groups show severely higher mean amounts of creatinine preoperatively in their blood serum (group A 137mg/dl, group B 136mg/dl). 1 year postoperatively these high results have been lowered slightly to 125mg/dl (group A) and 127mg/dl (group B). A rise in Pulmonary Capillary Wedge Pressure (PCWP) also strongly suggests failure of the left ventricular output. (26) Measuring the PCWP is a method of predicting the pressure within the left atrium. This procedure can be done through right heart catheterization and is less invasive then measuring directly in the left atrium. The normal PCWP pressure is 2-15mmHg and both groups show a preoperative mean PCWP of 26mmHg or higher. This indicates that the heart function in both groups is in bad condition and since there is just 2 mmHg of a difference between the groups they are for that matter equally situated. It is most certainly possible to state that the two groups are statistically not significantly different. On the other hand it is unfortunately not possible to state that the two groups show statistically significant differences 12-month postoperative yet. I included as many patients possible respecting the inclusion/exclusion criteria (Tab.1) but for strong statistically evaluation there are still not enough patients included. The setting of this study provides only limited patient availability, it is focused on one center and a rather recently developed novel implantation technique. Therefore until today only a few patients received the novel technique. To provide a slightly higher patient count I not only evaluated the 12-month survival but also the 10-month survival. Doing so allowed us to include another 13 patients to the population. In group A I had to exclude 5 patients because they received a heart transplantation within that time and therefore had no LVAD anymore. In group B there was 1 patient who had to be excluded for the same reason. By doing this it was possible to include another 12 minimally invasive implanted patients and one conventional treated patient. This shows not only the high number of patient’s receiving an HVAD in the MHH within two month but also that there are already more patients being treated with the minimally invasive technique rather than with the conventional approach. The results of the 10-month survival analysis are visualized in figure 10. Most eye-catching in this figure is the black curve, which represents the survival rate of end-stage heart failure patients who have only been treated with the best available medical therapy. (23) The brown curve shows the results of a continuous flow left ventricular assist devices by slaughter et al. (14) Slaughter et al. compared the pulastile vs. continuous flow LVAD pumps and published his results, stating that continuous flow LVAD treatment shows a significantly better survival rate then the pulsatile devices. The 10-month survival rate of about 30% in patients who received only medical therapy is stunningly low. The 10 month survival count in the group of patients treated with a continuous flow reaches about 80% which can only be topped through the survival rate of minimally invasive implanted HVAD (continuous flow pump) supported patients in my study. The 10-month survival rate as presented through the green curve in figure 7 shows 87%. There is a difference in survival of 22% between group A (65%) and group B (87%) from my evaluated population. This results in a p value of 0,043 and is therefore stated to be statistically significant higher in group B. The 10-month prolonging data has been censored through the


28

Kaplan Meier survival function and makes it therefore possible to provide data of 24-month postoperative even though not all patients have a 2 year follow up.


29

6. Conclusion

Even after several decades of research there still is no cure for end-stage heart failure, unfortunately the numbers of patients continue to rise. Heart transplantation still is the gold standard treatment (1,27) despite carrying major risk factors. Not only is the transplantation itself bound to a high rate of severe complications but also life after transplantation. The risk of rejection of the donor heart and the results of suppressing the immune system are major concerns. Mechanical circulatory support, especially left ventricular assisting devices, have been used and further developed for over 50 years now. Still this treatment is limited to severely ill patients as ultima ratio treatment. LVAD surgery has a huge impact on the patient body and carries high chances of developing severe complications. Because of this medical professionals only suggest this treatment whenever there is no other treatment available. But the cause of these high rates of complications is not the LVAD itself, it is the implantation procedure and the tremendously bad general health condition of the treated patients. Most of the LVAD-patients have a long history of insufficient blood circulation. These patients often present with severely compromised organ function, especially kidneys and liver. Through implanting the LVAD the circulation is restored to normal but in many cases the treatment comes to late. Throughout the years, the insufficient circulation has been major source of organ damage. Additionally there still is an outdated implantation procedure being used. The conventional total median sternotomy has been necessary in the past as it created a large chest opening, which was necessary to accommodate the older style devices, who were much larger. Today's third generation LVADs and HVADs are available with smaller dimensions. As proven many times in the past, a smaller opening has a smaller impact on the patients creating less risk and complications; the conventional surgical technique used in patients with severely compromised GSH is likely to have a high rate of complications. Thus the outcome of the patient depends not only on a safe implantation technique, but also on a reliable and technically sound pump and being able to treat the patient in the earlier stages in order to mitigate organ damage. Technical development and surgical experience made it possible to create this novel minimally invasive implantation technique. The data shows clearly that the novel implantation technique has a better outcome in survival then the conventionally used technique. Unfortunately there are currently an insufficient numbers of patients available to prove this outcome statistically. In this rather small cohort of patients I already have found significant differences comparing survival, postoperative bleeding, infections, RHF and the incidence of sepsis. Nevertheless both groups comprise severely ill patients who underwent implantation of the same device. Only the technique of implanting has been further developed and not the whole treatment. These facts should be kept in mind comparing the data between both groups. This is the first attempt of comparing both methods and it is most certainly not going to be the last. The results I have found are very promising warrant further investigation within a greater population. More patients need to be treated with the novel technique and need to be followed for a longer duration of time. The dimensions and reliability of the HVAD enables completely new treatment options. Not only is the implantation technique evolving, but research is being done on the treatment of right heart failure with the HVAD (RVAD). There is still a great range


30

of applying the HVAD that has not yet been fully established. Treating patients at an earlier stage of heart failure is expected to increase both the survival rate and the overall outcome.


31

7. Nederlands samenvatting

In deze studie hebben wij 66 patiënten onderzocht. Allemaal hebben de diagnose geavanceerd hartfalen gekregen en worden hiervoor behandelt. De patiënten worden allemaal tussen 29. Januari 2010 tot 21. Maart 2012 chirurgisch in de MHH met een LVAD verzorgd. Alle patiënten hebben een HVAD van HeartWare ontvangen doormiddel van twee verschillende chirurgische technieken. In 2011 werd een nieuwe, minimaal invasieve techniek door chirurgen van de MHH ontworpen. De uitkomst van de nieuwe techniek hebben wij vergeleken met de conventionele totale mediaan sternotomie. De geëvalueerde patiënten worden opgedeeld in twee groepen. Group A heeft doormiddel van de conventionele methode het HVAD geïmplanteerd gekregen en groep B ontving de minimaal invasieve techniek. Het is een retrospectief onderzoek waardoor wij alleen de bestaande gegevens konden vergelijken. Wij hebben alle patiënten die aan de criteria hebben voldaan opgenomen in deze studie. Het was mogelijk 37 patiënten in de conventionele groep A op te nemen en 29 patiënten hebben doormiddel van de nieuwe techniek hun HVAD ontvangen en zijn opgenomen in groep B. Preopertief was er geen statistisch significant verschil aan te tonen tussen de groepen. Postoperatief hebben wij beide groepen over 12 maanden gevolgd en hebben een verschil kunnen aantonen betreffend de overleving na 12 maand. In groep A hebben 31/37 patiënten de eerste 12 maanden postoperatief overleefd en in groep B waren het 27/29. Dat is een percentage van 84% in groep A vs. 93% 12 maand overleving in groep B. Het is nog niet statistisch aan te tonen dat dit verschil significant is, de P waarde ligt bij 0,45. De groepen zijn met 37/29 nog te klein voor een betrouwbare statistische evaluatie. De nieuwe techniek bestaat pas sinds 2011 en er worden steeds meer patiënten hiermee behandeld. Ook al is het aantal patiënten in deze studie op dit moment nog klein, wordt het wel duidelijk, met het oog op de postoperatieve complicaties en de overleving, dat de minimaal invasieve techniek het beter doet dan de conventionele.


32

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2. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009 Jan 27;119(3):480–6.

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