CVAD COMPARISON OF VENTRICULAR ASSIST DEVICES. Background

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Ethan Potter
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1 CVAD COMPARISON OF VENTRICULAR ASSIST DEVICES Background Cardiovascular disease remains the #1 cause of death in the United States. Congestive heart failure (CHF) continues to increase in frequency and prevalence, even as the mortality from coronary artery disease and valvular disease decreases. In the United States alone more than two million outpatient CHF clinic visits occur per year at a cost of more than $10 billion annually. Failure to optimize outpatient management leads to added inpatient care, burdening the healthcare system and the individual patient with additional demands. Total annual direct costs for managing and treating heart failure approach 60 billion dollars, a significant part of national healthcare expenditures. The median survival of patients with new onset congestive heart failure (CHF) is 5 years. CHF affects some 4 to 5 million Americans, with approximately 500,000 new cases diagnosed each year. Coupled with the aging of the American population, CHF continues to present clinicians and policy makers with vexing clinical and financial complexities. Heart failure is a particularly important problem in the elderly population, where its prevalence is approaching 10%. In fact, more than 75% of patients with heart failure are older than 65 years of age. With the continued aging of the population, both the incidence and prevalence of heart failure are expected to increase. Heart failure is also the most frequent cause of hospitalization in those older than the age of 65 years. All of this has major healthcare legislative implications. With a medical care budget of more than $22 billion, the Veterans Health Administration (VHA) employs approximately 180,000 health care professionals at 163 hospitals, more than 800 community and facility-based clinics, 135 nursing homes, 43 domiciliaries, 206 readjustment counseling centers and various other facilities. In addition to its medical care mission, the veterans health care system is the nation's largest provider of graduate medical education and a major contributor to medical and scientific research ( As such, focused inquiry into effective care of Americans with CHF is a priority. CHF is a complex clinical disorder. Both systolic and diastolic heart failure are associated with high rates of morbidity, mortality and cost. New York Heart Association (NYHA) functional class assignment is widely recognized as a classification schema for

2 severity of CHF, and at any given time 30% of patients are at NYHA Class III or IV, indicating severe impairment in functional ability. Despite recent advances in pharmacologic therapy, the 1- to 2-year mortality rate is on the order of 40% to 50% for advanced heart failure and the 4- to 5-year mortality rate ranges from 15% to 40% for those with asymptomatic left ventricular (LV) dysfunction or only mild to moderate symptoms. Although pharmacologic therapy can ameliorate CHF symptoms and slow disease progression, limitations exist. These include patient compliance with complex medical regimens and access issues relating to cost of newer therapies (including natriuretic peptides). For severe end-stage disease, cardiac transplantation provides long-term (10 year) survival now approaching 50%, and is the therapy of resort for patients failing medical management. The downstream effect of this is seen in the number of patients awaiting cardiac transplantation each year, a number limited by the critical shortage of donors. Research into cardiac assist devices was given momentum in the 1970s, when NHLBI began funding research that resulted in the development of intra-abdominal left ventricular assist devices (ALVADs). While clinical outcomes were initially discouraging, progress was made, and the use of such devices as a temporizing measure for patients awaiting transplantation was FDA approved. Several iterations of these assist devices have been developed. The study entitled Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) was conducted from 1998 through July 2001 in 20 cardiac transplant centers in the U.S. Involving 129 patients with end-stage heart failure who had not responded to medical management and were ineligible for cardiac transplantation, this randomized trial showed significant extension of life and improvement in quality for a subset of heart failure patients. This has added evidence to possible future clinical willingness to approach assist devices as permanent therapy itself, and as an extension or circumvention of the transplantation option. Also in discussion is the finding by a few clinicians that some CHF patients using mechanical circulatory assists devices apparently improve myocardial function and are able, after removal of the assist device, to achieve cardiac function better than baseline. Given all of this, further attention to the findings of the REMATCH study is warranted. The study was conducted at 20 experienced heart transplant centers. Eligible patients were adults with chronic endstage heart failure and with contraindications to heart failure. One type of vented electric device was selected for the study. This was the Heartmate LVAD (Thoratec Corporation; Pleasanton, CA). This device contains textured internal surfaces and patients receiving this do not require anticoagulation. Study patients were randomized in a 1:1 ratio to the vented electric system or optimal medical therapy. The primary endpoint was death from any cause. The trial was designed to enroll 140 patients and to continue until 92 deaths occurred. Secondary endpoints included the incidence of serious adverse events, the number of days of hospitalization, quality of life indices, symptoms of depression, and functional status. A total of 129 patients were enrolled. Sixty-eight received left ventricular assist devices and 61 were assigned to undergo optimal medical management. There was a reduction of 48% in the risk of death from any cause in the group that received the left ventricular devices, as compared with the

3 medical therapy group (P=0.001). The Kaplan-Meir estimates of survival at one year were 52 percent in the device group and 25 percent in the medical therapy group (P=0.002). At two years, these estimates were 23 percent and 8 percent, respectively (P=0.09). Terminal heart failure was the cause of most of the deaths in the medical therapy group, whereas most deaths in the device group were caused by sepsis (41%) and failure of the device (17%). Hence, despite substantial survival benefit, the mortality and morbidity associated with the device were considerable. Infection was a major limiting factor. Predisposing factors for infection included the status of the percutaneous drive line, malnutrition, and severe preoperative debilitation due to heart failure. Mechanical failure of the device, inflow valve insufficiency, and neurological events were the other major limiting factors. Clearly, in patients ineligible for transplantation, the left ventricular devices offer superior survival to optimal medical therapy. However, only one type of device was studied in REMATCH. The other commercially available left ventricular assist device (Novacor LVAS; World Heart, Inc.) has been used extensively as a bridge to transplant. This device does require anticoagulation, but may offer other features that reduce the incidence of infections and device failure. Device Descriptions The Heartmate (Thoratec, Pleasanton, Calif), is an implantable left ventricular assist device with a textured titanium surface. The pump was initially developed as a pneumatic pump and later adapted to an electrical powered system. The pump is powered by external battery source through percutaneous leads. The pump body is separated into the blood chamber and the actuating cam divided by the polyurethrane pusher plate. The cam is electromagnetically activated and pushes the plate via rotary motion. Unidirectional blood flow is maintained by porcine valves in the inflow and outflow conduits. The pump fills passively from the left ventricle and ejection occurs actively. The pump functions asynchronous to the cardiac electrical activity. The most important feature of this LVAD is a low incidence of thromboembolic events, even without concomitant anticoagulant therapy, such as coumadin. Most patients are maintained on aspirin alone. The reasons for this are not fully known, but may be due to the textured surfaces and/or poorly understood issues relating to blood / pump interaction and flow patterns within the device. Due to efficient draining of the left ventricle and ejection of blood into the ascending aorta, the aortic valve remains closed most of the time. Pump ejection force places considerable strain on the unsupported inflow valve. This has lead to some instances of inflow valve regurgitation. This may lead to increased LV pressure and symptoms of heart failure. However, due to poor filling and emptying of the pump, the rate increases and the calculated output is high, despite actual forward flow being low. This failure seems to occur often after one year. Also, blood / pump surface interactions are poorly defined. The incidence of pump failure was high in REMATCH, most notably after at least one year of use. Another problem has been infection. There seems to be increased susceptibility to infections, especially fungal. T cell abnormalities also have

4 been noted. Finally, the incidence of thromboembolic events was 10% in the REMATCH study in the device implanted patient group HEARTMATE DIAGRAM / PICTURE The Novacor LVAS is a left ventricular assist device that was initially developed as a fully implantable system for permanent therapy, and later adapted as a bridge to transplantation. The mechanism of the pump is unique. There are two opposed pusher plates actuated by an electromagnet. This then activates springs, allowing blood ejection. This unique process leads to a more physiologic ejection and can be synchronized to the native heart. Generally, the pump is placed in a synchronous counterpulsation mode. Also, the valves are in specially designed valve conduits to provide good support and physiological flows. In spite of these engineering designs, this pump has had a higher incidence of thromboembolic events, and requires careful anticoagulation. Recent studies have shown most of this relates to the length of and material used in the inflow conduit. Changes in the inflow conduit have significantly decreased the risk of thromboembolic events and may even lead to withdrawal of coumadin use. Most importantly, analysis of various pump parameters can be used to detect early pump bearing wear. This wear usually occurs between 3 to 5 years. As this is a gradual process, the pump can be replaced electively as opposed to emergently NOVACOR DIAGRAM / PICTURE These two important pumps, the Heartmate and the Novacor, have never been studied and compared prospectively as either bridges to transplantation or as destination therapies. These are the two pumps closest to application for destination therapy at this time and will serve well as benchmarks for future devices. Proposed Study Overview The findings in REMATCH ethically preclude further comparison of assist devices to medical therapy in late-stage heart failure patients. However, long-term effectiveness data are still unavailable for these devices. And robust, comparative data on the most widely used devices are unavailable. We propose a multi-year prospective, randomized clinical trial comparing the Heartmate and Novacor ventricular assist devices in patients with end-stage heart failure patients who are refractory to optimal medical therapy, and who are not cardiac transplant candidates. Primary endpoints include device reliability, infection rates at pre-defined intervals related to the device, and thromboembolic events. Secondary endpoints include overall mortality, nutritional status, & exercise capacity. A concurrent cost-effectiveness analysis (CEA) will be modeled and performed, utilizing the societal perspective. Quality of life issues and will be addressed utilizing subscales of the SF-36 & the Beck Depression Inventory.

5 We will use Cox proportional-hazards regression to estimate relative risks and confidence intervals. Analyses will be performed on an intention-to-treat basis. Based on preliminary power calculations, when the sample size in each group (Heartmate and Novacor) is 148, a level two-sided log rank test for equality of survival curves will have 80% power to detect the difference between a Group 1 proportion π1 at time t of 0.10 and a Group 2 proportion π2 at time t of 0.20 (a constant hazard ratio of 1.431); this assumes no dropouts before time t. PATIENT INCLUSION CRITERIA. 1. Advanced heart failure* of greater than 60 days refractory to optimal medical therapy (#). 2. Non-transplant candidates a. age greater than 60 y b. iddm with evidence of end organ damage c. creatinine > 2.0 but less than 4.0 for greater than 60 days d. FEV1 < 50% predicated e. Evidence of peripheral vascular disease f. Other physical or psychological/psychiatric factors that make transplantation not an option *Advanced heart failure. New Heart Association class IV status for at least 60 days with optimal medical therapy. Ejection fraction must be less than 25%. Must have a maximal oxygen consumption of less than 14 ml/kg/min with attainment of anaerobic threshold or have been resistant to weaning from intravenous inotrope therapy in the 14 days prior to randomization. Weaning must be met with hemodynamic compromize such as hypotension, decrease in renal function, or worsening of heart failure symptoms. Other exclusion criteria include use of an intra-aortic balloon pump and an inability to wean from such therapy in the 7 days prior to randomization. (#)Optimal Medical Therapy. Use of diuretics, meticulous identification and correction of fluid and salt retention. Use of digoxin and ace inhibitors unless contraindicated. Use of beta blockers and angiotensin converting enzyme blockers (with at least 60 days of continuous treatment). Withdrawal of drugs or agents known to adversely affect clinical status (non steroidal agents, most antiarrhythmics, calcium channel blockers, etc.). Correction of medical conditions that may exacerbate heart failure such as thyroid disease, pericardial disease. PATIENT EXCLUSION CRITERIA 1. Technical obstacles that pose an inordinate risk in the opinion of the certified surgeon. 2. Myocarditis.

6 3. Right ventricular failure, mean right atrial pressure greater than 20 mmhg. 4. Amyloidosis 5. Sarcoidosis 6. Pericardial disease 7. Uncorrected medical conditions such as thyroid disease, diabetes 8. Active infection within 7 days of randomization 9. Stroke within 60 days of randomization, or symptomatic extra- or intracranial vascular disease 10. Evidence of intrinsic hepatic disease with transaminases elevated to greater than 5 times normal within 7 days of randomization, INR greater than 1.5 that cannot be corrected, biopsy proven cirrhosis 11. Renal failure requiring dialysis 12. Presence of a mechanical aortic valve that cannot be replaced with a bioprosthesis, or severe aortic regurgitation that cannot be corrected 13. Evidence of intracardiac shunts that cannot be corrected 14. Confirmation by neurologist of impairment of cognitive function or irreversible dementia 15. Untreated abdominal aortic aneurysm greater than 5 cm 16. Abdominal surgery planned 17. Evidence of peripheral vascular disease with rest pain or imminent limb loss 18. Uncontrolled coagulopathy. 19. Tobacco, alcohol or drug abuse likely to impair compliance with study protocol 20. Pregnancy 21. Body mass index > 40 kg/m2 22. Body surface less than 1.5 m2 23. Receiving therapy with investigational intervention or participating in another clinical study. 24. Presence of condition other than heart failure that would limit survival to less than 3 years CVAD Research Team (Core) Principal Investigator: Vigneshwar Kasirajan, MD Hunter Holmes McGuire VA Medical Center Richmond, VA & Division of Cardiothoracic Surgery VCU Health System Richmond, VA Co PI: Shantaram Rangappa, MD, MSHA Division of Cardiology VCU Health System Richmond, VA

7 Study Personnel: Research Nurse: TBD Data Manager: TBD Staff Physicians: TBD Staff Nurses: TBD

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