REMATCH: LVADs for End-Stage Heart Failure (2001)

“The use of a left ventricular assist device in patients with advanced heart failure resulted in a clinically meaningful survival benefit and an improved quality of life. A left ventricular assist device is an acceptable alternative therapy in selected patients who are not candidates for cardiac transplantation.”

  • The REMATCH Investigators

1. Publication Details

  • Trial Title: Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure
  • Citation: Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-Term Use of a Left Ventricular Assist Device for End-Stage Heart Failure. N Engl J Med. 2001;345(20):1435-1443. DOI: 10.1056/NEJMoa012175
  • Published: November 15, 2001, in The New England Journal of Medicine
  • Author: Eric A. Rose, M.D., on behalf of the REMATCH investigators
  • Funding: The National Heart, Lung, and Blood Institute (NHLBI); Thoratec Corporation.

2. Keywords

  • Heart Failure, Left Ventricular Assist Device (LVAD), Mechanical Circulatory Support, Destination Therapy, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with end-stage heart failure who are ineligible for cardiac transplantation (Population), does implantation of a left ventricular assist device (LVAD) (Intervention) compared to optimal medical management (Comparison) reduce all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: End-stage heart failure refractory to medical therapy carried an extremely high mortality rate, with a 1-year survival of less than 25%. For patients who were not candidates for a heart transplant, there were no effective long-term treatment options.
  • Knowledge Gap: Left ventricular assist devices (LVADs) were used as a temporary “bridge to transplantation,” but it was unknown if these devices could be used as a permanent or “destination” therapy to improve survival in transplant-ineligible patients.
  • Proposed Hypothesis: The authors hypothesized that long-term LVAD therapy would be superior to optimal medical management in improving survival in patients with end-stage heart failure who were not candidates for transplantation.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 20 tertiary care cardiac surgery centers in the United States.
  • Trial Period: Enrollment ran from May 1998 to July 2001.
  • Population:
    • Inclusion Criteria: Adult patients with NYHA Class IV, end-stage heart failure, a left ventricular ejection fraction (LVEF) of <25%, who were not candidates for cardiac transplantation.
    • Exclusion Criteria: Included irreversible renal or liver failure and active infection.
  • Intervention: Patients were randomized to receive a pulsatile-flow left ventricular assist device (the HeartMate VE LVAD).
  • Control: Patients were randomized to receive optimal medical management, which included diuretics, ACE inhibitors, beta-blockers, and inotropes as needed.
  • Management Common to Both Groups: All patients received the best available medical and supportive care for heart failure.
  • Power and Sample Size: The authors calculated that a sample size of 140 patients would be required to have 90% power to detect a significant difference in survival. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality.
    • Secondary Outcomes: Included survival at 1 and 2 years, quality of life, and the incidence of adverse events.

6. Key Results

  • Enrollment and Baseline: 129 patients were randomized (68 to the LVAD group and 61 to medical therapy). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board after an interim analysis showed a clear and significant survival benefit in the LVAD group.
  • Primary Outcome: All-cause mortality was dramatically lower in the LVAD group. The risk of death from any cause was reduced by 48% in the LVAD group compared to the medical therapy group (p=0.001).
  • Secondary Outcomes: Survival at 1 year was 52% in the LVAD group vs. 25% in the medical-therapy group. Survival at 2 years was 23% vs. 8%. Patients in the LVAD group also reported a significant improvement in their quality of life.
  • Adverse Events: The incidence of serious adverse events was significantly higher in the LVAD group. These were primarily device-related infections (occurring in 28% of patients), bleeding, and device malfunction.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a time-to-event analysis with a log-rank test.
  • Primary Outcome Analysis: The primary outcome was a comparison of survival over time between the two groups.
  • Key Statistic(s) Reported: Hazard Ratio (HR) for death from any cause: 0.52 (95% CI, 0.34 to 0.78; P-value: 0.001).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR):
      • Formula: Conceptually, HR = (Hazard Rate in Intervention Group) / (Hazard Rate in Control Group).
      • Calculation: The paper reports the result as 0.52.
      • Clinical Meaning: The HR of 0.52 means that patients in the LVAD group had a 48% lower risk of dying at any given time point compared to the medical-therapy group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.34 to 0.78.
      • Clinical Meaning: Since this entire range is well below the line of no effect (1.0), it confirms that the result is highly statistically significant.
    • P-value: The p-value of 0.001 is well below the 0.05 threshold, indicating the result is highly statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR) (for 1-year mortality):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = (100% – 25%) – (100% – 52%) = 75% – 48% = 27%.
      • Clinical Meaning: For every 100 patients treated with an LVAD, 27 additional patients were alive at 1 year.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.27 = 3.7, which is rounded down to 3.
      • Clinical Meaning: You would only need to treat 3 to 4 patients with an LVAD to save one additional life at 1 year.
  • Subgroup Analyses: The benefit was consistent across subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided a high level of evidence for a novel and life-saving therapy.
  • Generalizability: The inclusion of 20 diverse cardiac surgery centers increases the applicability of the findings.
  • Statistical Power: Although stopped early, the trial was large enough to detect a clear and significant effect.
  • Patient-Centered Outcomes: The study focused on the most important patient-centered outcomes: survival and quality of life.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label, which is an unavoidable limitation for a major surgical intervention.
  • External Validity (Generalizability): The findings are specific to the first-generation, pulsatile-flow LVAD used in the trial, which has since been replaced by newer, more durable devices.
  • Other: The trial was stopped early for benefit, which can sometimes lead to an overestimation of the true treatment effect. The very high rate of device-related complications is a major limitation.

10. Conclusion of the Authors

  • The authors concluded that the use of a left ventricular assist device in patients with advanced heart failure resulted in a clinically meaningful survival benefit and an improved quality of life, and that it is an acceptable alternative therapy for selected patients who are not candidates for cardiac transplantation.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided the definitive evidence that established long-term mechanical circulatory support (“destination therapy”) as a new standard of care for patients with end-stage heart failure who are not eligible for a transplant.
  • Specific Recommendations:
    • Patient Selection: For adult patients with end-stage, NYHA Class IV heart failure who are not candidates for transplantation.
    • Actionable Intervention: Offer implantation of a left ventricular assist device.
    • Expected Benefit: This intervention can be expected to save one additional life for every 3-4 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that LVADs are a cure for heart failure or that they are without significant risk.
  • Implementation Caveats: The key takeaway is the critical trade-off between a major survival benefit and a very high risk of serious, device-related complications. This requires a highly specialized, multidisciplinary team and a detailed shared decision-making process with the patient and family.

12. Context and Related Studies

  • Building on Previous Evidence: The REMATCH trial (2001) was the first large RCT to test the concept of “destination therapy” for a patient population that previously had no long-term treatment options.
  • Influence on Subsequent Research: The definitive positive result of this trial, despite the high complication rate, spurred a massive wave of innovation in the field of mechanical circulatory support. This led directly to the development of smaller, quieter, more durable continuous-flow LVADs (e.g., HeartMate II, HeartMate 3), which have been evaluated in subsequent, large randomized trials.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question from this trial was how to reduce the high burden of device-related complications.
  • Future Directions: The entire subsequent generation of continuous-flow LVADs and the trials that have studied them (e.g., comparing HeartMate II to HeartMate 3) can be seen as the future direction that followed from this seminal trial.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, testing a novel, life-saving therapy for a terminal condition with no other treatment options.
  • Methods: The multicenter RCT design was appropriate and robust. The main methodological weakness is the open-label design, which is unavoidable for this type of intervention.
  • Results: The study reported a statistically significant and clinically profound survival benefit (NNT of ~4). The finding of a very high rate of serious adverse events was a critical counterpoint to this benefit.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in the history of cardiology and critical care, establishing a completely new therapeutic paradigm. Its findings, while specific to an older device, created the foundation for the entire modern field of destination therapy LVADs.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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