REMATCH

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Rose EA, et al. "Advanced heart failure treated with continuous-flow left ventricular assist device". The New England Journal of Medicine. 2001. 345(20):1435-1443.
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Clinical Question

In patients with end-stage heart failure, do left ventricular assist devices reduce all-cause mortality, as compared to optimal medical therapy?

Bottom Line

In patients with end-stage heart failure, left ventricular assist devices reduce all-cause mortality, as compared to optimal medical therapy.

Major Points

Left ventricular assist devices (LVAD) were first developed as a short-term mechanical circulatory support therapy for patients with end-stage heart failure as a bridge to cardiac transplantation. However, the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial aimed to determine the suitability of LVAD for destination therapy. In the trial, pulsatile-flow LVAD (HeartMate XVE, Thoratec, Pleasanton, Calif.) was compared to optimal medical therapy (OMT), with the primary endpoint being all-cause mortality. [1]

Patients with advanced heart failure (NYHA class IV, LVEF ≤25%) who were ineligible for cardiac transplantation were randomized to receive LVAD (n=68) or optimal medical therapy (n=61). The trial showed that LVAD was associated with a 48% reduction in mortality as compared with optimal OMT (relative risk 0.52, 95 % CI 0.34-0.78, P=0.001). The survival at 1 year in the LVAD group was 52% as compared to 25% in OMT (P=0.002; NNT=4). However, the difference was diminished at 2 years (23% and 8% in LVAD and OMT group, respectively; P=0.09). It is also important to note that the incidence of serious adverse events in the LVAD group was significantly higher as compared to the OMT group (rate ratio 2.35; 95% CI 1.86-2.95).

Published in 2007, the INTrePID trial, also showed a significant survival advantage with LVAD for destination therapy in patients with inotrope-dependent heart failure, as compared to OMT. [2] In 2009, the HEARTMATE II trial reported compared the newer continuous-flow LVAD (HeartMate II) with pulsatile-flow LVAD. Similarly, patients with end-stage heart failure on OMT who were ineligible for cardiac transplantation were recruited. The study reported 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-flow LVAD group; hazard ratio 0.38, 95% CI 0.27-0.54, P<0.001).[3]

Guidelines

AHA/ACCF Heart Failure Guidelines (2013, adapted)[4]

  • 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=129
    • LVAD (n=68)
    • OMT (n=61)
  • Setting: 20 centers in the United States
  • Enrollment: March 1998-July 2001
  • Follow-up: 2 years
  • Analysis: intention-to-treat
  • Primary outcome: all-cause mortality

Population

Some criteria are presented elsewhere.[5]

Inclusion Criteria

  • age >18 years
  • NYHA Class IV heart failure symptoms for 90 days despite therapy with ACE inhibitors, diuretics, and digoxin
  • left ventricular EF ≤25%
  • peak oxygen consumption ≤12 ml/kg/min
  • persistent requirement for intravenous inotrope due to symptomatic hypotension, worsening renal function, or pulmonary edema
  • ineligible for cardiac transplant due to one of the following reasons:
    • age >65 years
    • diabetes mellitus requiring insulin and complicated by end-organ damage
    • CKD with a serum creatinine >2.5 mg/dL (221 μmol/L) for ≥90 days prior to randomization
    • other significant conditions

The criteria were broadened 18 months into enrollment to include:

  • NYHA class IV heart failure symptoms for 60 days
  • peak oxygen consumption ≤14 ml/kg/min
  • NYHA class III or IV heart failure for ≥28 days and received ≥14 days of support with an intraaortic balloon pump or IV inotropes

Exclusion Criteria

  • heart failure due to or associated with uncorrected thyroid disease, obstructive cardiomyopathy, pericardial disease, amyloidosis, or active myocarditis
  • high surgical risk
  • INR ≥1.3 or prothrombin time >15 seconds within 24 hours prior to randomization
  • body surface area < 1.5 m2
  • BMI >40 kg/m2
  • COPD (FEV ≤ 1.5 L/min)
  • pregnancy
  • fixed pulmonary hypertension with pulmonary vascular resistance ≥ 8 Wood units refractory to pharmacologic intervention, within 90 days prior to randomization
  • under consideration for revascularization, therapeutic valvular repair, left ventricular reduction procedure, or cardiomyoplasty
  • cardiac transplantation, left ventricular reduction procedure, or cardiomyoplasty
  • mechanical aortic valve at the time of LVAD implant
  • other ongoing mechanical circulatory support than IABP
  • AST, ALT or total bilirubin >5x upper limit of normal, or liver cirrhosis (proved by biopsy)
  • stroke ≤90 days prior to enrollment, cerebrovascular disease with significant (>80%) extracranial stenosis
  • impairment of cognitive function
  • untreated aortic aneurysm ≥5 cm 30 days prior to randomization
  • systemic infection 48 hours prior to randomization
  • platelet ≤50,000 mm3  24 hours prior to randomization
  • serum creatinine ≥3.5 mg/dL or chronic renal replacement therapy
  • severe peripheral vascular disease
  • use of calcium channel blocker (except amlodipine), or a class I or III antiarrhythmic ≤28 days prior to enrollment
  • planned abdominal surgery
  • psychiatric disease that is likely to impair with compliance to study protocol
  • survival <3 years due to a condition other than heart failure
  • participating in another clinical study
  • receiving an investigational therapy

Baseline Characteristics

From the LVAD group (n=68)

  • Demographics: age 66±9.1 years, male 78%
  • Clinical measurements: systolic BP 101±15 mm Hg, diastolic BP 61±10 mm Hg; heart rate 84±16 beats/min
  • Cardiac measurements: LVEF 17±5.2%, PCWP 25±9.9 mm Hg, cardiac index 1.9±0.99 L/min/m2 of BSA, pulmonary vascular resistance 3.4±1.8 Wood units, CVP 13±6 mm Hg
  • Medical history: Heart failure due to ischemia 78 %, stroke 16%
  • Treatment: ACE-inhibitor 62%, ARB 10%, beta-blocker 24%, loop diuretic 96%, spironolactone 34%, IV inotrope 65%, digoxin 87%, amiodarone 45%
  • Laboratory results: creatinine: 1.7±0.65 mg/dL, sodium 135.7±5.4 mmol/L
  • Quality of life: Minnesota Living with Heart Failure score 75±18; SF-36-Physical function 19±19, emotional role 33±42; Beck Depression Inventory 19±9

Interventions

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

Pulsatile-flow HeartMate XVE (Thoratec)
  • device volume 450 ml, weight 1250 grams
  • the device was implanted in either the preperitoneal pocket or intraperitoneal cavity, depending on the surgeon's preference
Optimal medical therapy
  • treatment with digoxin, diuretics, and ACE-inhibitor (ARB if intolerant)
  • beta-blocker treatment is dependent on the investigator's discretion

Outcomes

Outcomes are presented as LVAD vs. OMT

Primary Outcome

All-cause mortality
48% reduction in the LVAD group (relative risk 0.52; 95% CI 0.34-0.78; P=0.001)
Survival at 1 year: 52% vs. 25% (P=0.002; NNT=4)
Survival at 2 years: 23% vs. 8% (P=0.09)


Secondary Outcomes

All serious adverse events
6.45 vs. 2.75 rate/patient-year (rate ratio 2.35, 95% CI 1.86-2.95)
  • Neurological (including stroke, TIA, and toxic, or metabbolic encephalopathy)
0.39 vs. 0.09 rate/pt-yr (rate ratio 4.35, 95% CI 1.31-14.50)
  • Bleeding (non-neurologic)
0.56 vs. 0.06 rate/pt-yr (rate ratio 9.47, 95% CI 2.30-38.90)
  • Infection
local: 0.39 vs. 0.24 rate/pt-yr (rate ratio 1.63, 95% CI 0.72-3.70)
sepsis: 0.6 vs. 0.3 rate/pt-yr (rate ratio 2.03, 95% CI 0.99-4.13)
  • Other organ dysfunction
renal failure: 0.25 vs. 0.18 rate/pt-yr (rate ratio 1.42, 95% CI 0.54-3.71)
hepatic failure: 0.02 vs. 0 rate/pt-yr
  • Cardiovascular
cardiac arrest: 0.12 vs. 0.18 rate/pt-yr (rate ratio 0.65, 95% CI 0.21-2.00)
supraventricular arrhythmia: 0.12 vs. 0.03 rate/pt-yr (rate ratio 3.92, 95% CI 0.47-32.40)
ventricular arrhythmia: 0.25 vs. 0.56 rate/pt-yr (rate ratio 0.45, 95% CI 0.22-0.9)
non-perioperative myocardial infarction: 0.02 vs. 0.03 rate/pt-yr (rate ratio 0.65, 95% CI 0.04-10.30)
peripheral thromboembolism: 0.14 vs. 0.06 rate/pt-yr (rate ratio 2.29, 95% CI 0.48-10.80)
syncope: 0.04 vs. 0.03 rate/pt-yr (rate ratio 1.31, 95% CI 0.12-14.40)
  • LVAD-related events
suspected malfunction: 0.75 rate/pt-yr
LVAD failure: 0.08 rate/pt-yr
perioperative bleeding: 0.46 rate/pt-yr
drive-line tract or pocket infection: 0.41 rate/pt-yr
pump interior, inflow, or outflow tract infection: 0.23 rate/pt-yr
right heart failure: 0.17 rate/pt-yr
thrombosis in LVAD: 0.06 rate/pt-yr
perioperative MI: 0 rate/pt-yr
Days spent in the hospital
88 vs. 24 days (P-value not reported)
Quality of life and functional status at 1-year, assessed by
Minnesota Living with Heart Failure questionnaire: 41±22 vs. 58±21 (P=0.11)
SF-36 physical function: 46±19 vs. 21±21 (P=0.01)
SF-36 emotional role: 64±45 vs. 17±28 (P=0.03)
Beck Depression Inventory: 8±7 vs. 13±7 (P=0.04)

Other outcomes

Causes of death
There were 41 and 54 deaths in the LVAD and OMT group, respectively
In the LVAD group, the most common cause (41.5%) was sepsis. Other causes include LVAD failure (17.1%), cerebrovascular disease (9.8%), and pulmonary embolism (4.9%).
In the OMT group, the most common cause (92.6%) was left ventricular dysfunction.


Subgroup analysis

The trial was not designed for subgroup analyses due to insufficient statistical power. However, the authors reported the following prespecified analysis for the primary outcome

Age
18-59 years: No significant difference
60-69 years: Favors LVAD (relative risk 0.49; 95% CI, 0.25-0.95)
≥70 years: No significant difference

Criticisms

  • It is important to note that survival at 2 years is suboptimal in patients who received LVAD. Therefore the effect of LVAD on quality of life needs to be carefully mesaured as it is an important factor supporting the use of mechanical circulatory support. [6]
  • The cost for LVAD therapy needs to be considered before deciding that it is a suitable alternative to medical therapy.[7]
  • The causes of death need to be considered. While 93% of deaths in the OMT group were due to heart failure, common causes of death in the LVAD group included sepsis, pulmonary embolism, and bleeding all of which may occur immediately post-operation.[7]

Funding

  • The National Heart, Lung, and Blood Institute
  • Thoratec

Further Reading

  1. Rogers JG et al. Chronic mechanical circulatory support for inotrope-dependent heart failure patients who are not transplant candidates: results of the INTrEPID Trial. J. Am. Coll. Cardiol. 2007. 50:741-7.
  2. Rogers JG et al. Chronic mechanical circulatory support for inotrope-dependent heart failure patients who are not transplant candidates: results of the INTrEPID Trial. J. Am. Coll. Cardiol. 2007. 50:741-7.
  3. 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.
  4. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.
  5. Rose EA, Moskowitz AJ, Packer M, et al. The REMATCH trial: rationale, design, and end points: Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure. Ann Thorac Surg 1999;67:723-730
  6. Hauptman PJ. Left ventricular assist device. N Engl J Med. 2002;346(13):1023-5; author reply 1023-5
  7. 7.0 7.1 Alpert JS. Left ventricular assist devices reduced the risk for death and increased 1-year survival in chronic end-stage heart failure. ACP J Club. 2002;136(3):88