HEARTMATE II

Published

Slaughter MS, et al. "Advanced heart failure treated with continuous-flow left ventricular assist device". The New England Journal of Medicine. 2009. 361(23):2241-2251.
PubMed • Full text • PDF

Clinical Question

In patients with advanced heart failure, do continuous-flow left ventricular assist devices improve survival free from disabling stroke and device failure, as compared with pulsatile devices?

Bottom Line

In patients with advanced heart failure, continuous-flow left ventricular assist devices improve survival free from disabling stroke and device failure, as compared with pulsatile devices.

Major Points

The REMATCH and INTrEPID Trial evaluated the role of left ventricular assist device (LVAD) in patients with advanced heart failure who are ineligible for heart transplant. In the REMATCH trial, patients who received LVAD had a 48% reduction in mortality as compared with medical-therapy (OMT) (relative risk 0.52, 95 % CI 0.34-0.78, P=0.001). Similarly, the INTrePID trial showed a significant survival advantage with LVAD as compared to OMT. The LVAD used in these studies were pulsatile-flow devices with a larger size and less durability as compared to new continuous-flow LVAD. In the HEARTMATE II study, continuous-flow LVAD (HeartMate II, abbreviated as HMII) was compared to pulsatile-flow LVAD (HeartMate XVE) for destination therapy, with the primary endpoint of 2-year survival free from disabling stroke and LVAD failure.

Patients with advanced heart failure (NYHA class III or IV, LVEF ≤25%) treated with OMT who were ineligible for heart transplant were randomized to receive continuous-flow LVAD (n=134) or pulsatile-flow LVAD (n=66). The trial showed that continuous-flow LVAD was associated with increased probability of 2-year survival free from disabling stroke and LVAD failure (46% vs. 11% in pulsatile-LVAD group; hazard ratio 0.38, 95% CI 0.27-0.54, P<0.001). Continuous-flow LVAD was also associated with significantly less major adverse events, including infection (device- and non-device related), right heart failure and arrhythmia. The rate of hospitalization was also significantly reduced.

The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis published in 2014 analyzed the data from 6,912 patients who received a HMII LVAD between 2006-2013. The overall survival was 80% at 1 year and 69% at 2 years. The reported incidence of HMII device thrombosis has varied between 0.01-0.12 events/patient-years. As reinforced in a systematic review published in 2015, continuous-flow LVAD has led to improvements in survival and quality of life. However, there is a significant risk of adverse events including bleeding, neurological events, and infection which needs to be carefully considered.

Guidelines

AHA/ACCF Heart Failure Guidelines (2013, adapted)

• Mechanical circulatory support (MCS) can be considered in selected patients with stage D HFrEF with planned definitive management (eg, cardiac transplantation) or cardiac recovery planned. (Class IIa, Level B)
• Nondurable MCS is reasonable as a “bridge to recovery” or “bridge to decision” for selected patients with HFrEF with acute, profound hemodynamic compromise. (Class IIa, Level B)
• Durable MCS is reasonable to prolong survival for selected patients with stage D HFrEF(672–675) (Class IIa, Level B)
  • Selection criteria for patients include: LVEF<25% and NYHA class III-IV despite optimal medical therapy, and either high predicted 1- to 2-year mortality (eg, markedly reduced peak oxygen consumption and clinical prognostic scores) or dependence on continuous parenteral inotropic support

Design

• Multicenter, prospective, randomized, controlled trial
• N=200
  • Continuous-flow LVAD (n=134)
  • Pulsatile-flow LVAD (n=66)
• Setting: 38 centers in the United States
• Enrollment: March 2005-May 2007
• Follow-up: 2 years
• Analysis: Intention-to-treat
• Primary outcome: 2-year survival free of disabling stroke (Rankin score >3) or device replacement

Population

Inclusion Criteria

• age ≥18 years
• advanced heart failure (Class IIIB or IV), and meeting 1 of the following criteria:
  • failing to respond to optimal medical therapy for ≥45 out of the last 60 days
  • Class III or Class IV heart failure for ≥14 days, and dependent on intra-aortic balloon pump (IABP) for 7 days and/or inotropes for ≥14 days
  • intolerant to ACE inhibitors or beta-blockers after treatment for ≥30 days
• left ventricular EF ≤25%
• peak oxygen consumption ≤14 ml/kg/min or <50% of predicted
• ineligible for cardiac transplant
• body-surface area ≥1.5m²

Exclusion Criteria

• heart failure due to or associated with uncorrected thyroid disease, obstructive cardiomyopathy, pericardial disease, amyloidosis, active myocarditis or restrictive cardiomyopathy
• high surgical risk
• other ongoing mechanical circulatory support than IABP
• BMI >40 kg/m²
• pregnancy
• mechanical aortic valve at time of LVAD implant
• cardiac transplant or cardiomyoplasty
• platelet ≤50,000
• untreated aortic aneurysm ≥5cm
• uncontrolled, active infection
• perceived difficulty complying with study protocol
• intolerance to peri-operative therapy, including anticoagulant or antiplatelet
• INR ≥2.5 (except due to anti-coagulant)
• clopidogrel use within 5 days
• severe COPD or restrictive lung disease
• AST, ALT or total bilirubin >5x upper limit of normal, or liver cirrhosis (proved by biopsy)
• pulmonary hypertension with PVR ≥8 Wood units that is not responsive to pharmacological intervention
• stroke ≤90 days prior to enrollment, cerebral vascular disease with significant (>80%) extracranial stenosis
• creatinine ≥3.5 mg/dl or chronic renal replacement therapy
• severe peripheral vascular disease
• moderate to severe aortic insufficiency without plans for correction during LVAD implantation
• use of calcium channel blocker (except amlodipine), or a class I or III antiarrhythmic (except amiodarone) ≤28 days prior to enrollment
• survival <3 years

Baseline Characteristics

From the continuous-flow LVAD group

• Demographics: age 62±12 years, male 81%
• Clinical measurements: body-surface area 2.0±0.3 m²; systolic BP 104±14 mm Hg, diastolic BP 61±13 mm Hg
• Cardiac measurements: LVEF 17.0±5.5%, PCWP 24±8 mm Hg, cardiac index 2.0±0.6 L/min/m² of BSA, pulmonary vascular resistance 264±128 dyn•sec•^-5, CVP 13±6 mm Hg
• Medical history: Heart failure due to ischemia 66%, stroke 16%
• Treatment: ACE-inhibitor 32%, ARB 9%, beta-blocker 53%, diuretic 92%, IV inotrope 77%; ICD 83%, IABP 22%, mechanical ventilation 7%
• Laboratory results: creatinine: 1.6±0.6 mg/dL, sodium 134.7±4.3 mmol/liter
• Destination therapy risk score: 10.4±5.4; high or very high risk patients 18%

Interventions

Patients were randomized in a 2:1 ratio to 2 groups:

Continuous-flow HeartMate II (Thoratec)

• device volume 63 ml, weight 390 grams
• antithrombotic management: aspirin and warfarin (INR 2-3)

Pulsatile-flow HeartMate XVE (Thoratec)

• device volume 450 ml, weight 1250 grams
• antithrombotic management: aspirin

Outcomes

Comparisons are continuous-flow LVAD vs. pulsatile-flow LVAD

Primary Outcome

Survival free from reoperation to repair or replace LVAD and disabling stroke at 2 years

46% vs. 11% (P<0.001)

Secondary Outcomes

Disabling stroke

11% vs. 12% (HR 0.78, 95% CI 0.33-1.82, P=0.56)

Reoperation to repair or replace LVAD

10% vs. 36% (HR 0.18, 95% CI 0.09-0.37, P<0.001)

Mortality within 2 years after LVAD implant

33% vs. 41% (HR 0.59, 95% CI 0.35-0.99, P=0.048)

Disabling stroke, mortality, and reoperation to repair or replace LVAD within 2 years

54% vs. 89% (HR 0.38, 95% CI 0.27-0.54, P<0.001)

Actuarial survival

1-year survival: 68% vs. 58%

2-years survival: 55% vs. 24%

RR 0.54; 95% CI 0.34-0.86, P=0.008

Quality of life at 1-year post LVAD implant, assessed by

Minnesota Living with Heart Failure questionnaire: 34.1±22.4 vs. 44.4±23.2 (P=0.03)

Kansas City Cardiomyopathy questionnaire: 65.9±20.0 vs. 59.1±20.3 (P=0.06)

Adverse Events

Neurological

ischemic or hemorrhagic stroke: 0.13 vs. 0.22 events/patient-year (HR 0.59, 95% CI 0.26-1.35, P=NS)

ischemic stroke: 0.06 vs. 0.1 events/pt-yr (HR 0.59, 95% CI 0.18-1.92)

hemorrhagic stroke: 0.07 vs. 0.12 events/pt-yr (HR 0.59, 95% CI 0.20-1.71)

TIA and other non-stroke events: 0.17 vs. 0.29 events/pt-yr (HR 0.57, 95% CI 0.28-1.20)

Bleeding

requiring transfusion: 1.66 vs. 2.45 events/pt-yr (HR 0.68, 95% CI 0.46-1.02)

requiring surgery: 0.23 vs. 0.29 events/pt-yr (HR 0.80, 95% CI 0.39-1.64)

Infection

any device component: 0.48 vs. 0.90 events/pt-yr (HR 0.53, 95% CI 0.32-0.88)

percutaneous lead: 0.38 vs. 0.61 events/pt-yr (HR 0.63, 95% CI 0.36-1.10)

pump pocket: 0.09 vs. 0.24 events/pt-yr (HR 0.37, 95% CI 0.16-0.86)

pump housing: 0.00 vs. 0.05 events/pt-yr (HR 0.1, 95% CI 0.01-1.11)

local: 0.76 vs. 1.33 events/pt-yr (HR 0.57, 95% CI 0.36-0.90)

sepsis: 0.39 vs. 1.11 events/pt-yr (HR 0.35, 95% CI 0.21-0.57)

Cardiovascular

right heart failure: 0.16 vs. 0.53 events/pt-yr (HR 0.30, 95% CI 0.16-0.57)

arrhythmia: 0.69 vs. 1.31 events/pt-yr (HR 0.53, 95% CI 0.33-0.83)

myocardial infarction: 0 vs. 0.02 events/pt-yr

peripheral thromboembolism: 0.10 vs. 0.19 events/pt-yr (HR 0.52, 95% CI 0.21-1.25)

Other organ dysfunction

respiratory failure: 0.31 vs. 0.80 events/pt-yr (HR 0.39, 95% CI 0.23-0.66)

renal failure: 0.10 vs. 0.34 events/pt-yr (HR 0.30, 95% CI 0.14-0.63)

hepatic dysfunction: 0.01 vs. 0 events/pt-yr

Other

pump replacement: 0.06 vs. 0.51 events/pt-yr (HR 0.12, 95% CI 0.06-0.26)

device thrombosis: 0.02 vs. 0 events/pt-yr

hemolysis: 0.02 vs. 0 events/pt-yr

psychological: 0.05 vs. 0.10 events/pt-yr (HR 0.54, 95% CI 0.16-1.78)

rehospitalization: 2.64 vs. 4.65 events/pt-yr (HR 0.62, 95% CI 0.41-0.93)

Criticisms

• Open-label trial allows potential for bias
• Trial patients were specifically selected therefore it is not certain if the results can be applied to the general population of patients with heart failure
• Several centers had limited experience with the continuous-flow LVAD before the study commenced
• As evidenced by the adverse event rates reported by the study, patients need to be made aware that the risk is substantial. This is particularly important in the setting of end-of-life care

Funding

• Thoratec