Effectiveness of LVAD vs Medical Management in Ambulatory HF
A total of 200 patients were enrolled in the study for LVAD DT support (n = 97) or continuing on OMM (n = 103) (Table 1, Figure 1). Most subjects were men with a median age of 65 years (range 21 to 82 years). Many baseline parameters were characteristic of a patient population with advanced HF and were overall similar between the LVAD and OMM groups. However, patients in the LVAD group compared with the OMM group were more severely ill (NYHA functional class IV: 52% vs. 25%; INTERMACS profile 4: 65% vs. 34%), had lower baseline HRQol, had more severe depression (87% vs. 60% [at least mild depression]), and had lower predicted Seattle Heart Failure Model 12-month survival rates.
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Figure 1.
The ROADMAP Patients at 1 Year
Flow chart depicts outcomes and events within 12 months of enrollment in the ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device [LVAD] and Medical Management) trial. Patients who withdrew from the study or received an elective heart transplant within 1 year were excluded from the primary endpoint analysis. *12 optimal medical management (OMM) patients missing 6-min walk distance data were excluded from the primary endpoint analysis. †8 left ventricular assist device (LVAD) patients missing 6MWD data were excluded from the primary endpoint analysis. ‡Includes 1 elective and 2 urgent transplants.
Patient questionnaires at baseline demonstrated that more LVAD patients reported that they were not satisfied or only slightly satisfied with their quality of life on baseline medical therapy (79%) compared with those who remained on OMM (48%) (Table 2). Significantly more LVAD patients at baseline also reported a perception that they were going to live <1 year (53% vs. 9%). The main patient reasons given for choosing OMM instead of LVAD include not wanting major device surgery, not wanting to depend on a machine, and not feeling sick enough (Table 3). For patients who agreed to LVAD therapy, the main reasons given were anticipated improvement in survival and improvements in quality of life and HF symptoms.
A flow chart of all patients and outcomes over the first year is shown in Figure 1. Of the 103 OMM patients, 18 died, 18 received a delayed LVAD at least 1 month after enrollment (including 1 patient receiving a total artificial heart), and 9 patients withdrew from the study before reaching an outcome, leaving 58 patients alive on original OMM therapy at 12 months. The median time from enrollment to delayed LVAD was 138 days (quartiles 1 to 3: 72 to 203 days). For the 97 patients in the LVAD arm, 17 died, 3 received a heart transplant (2 urgent and 1 elective), and 3 withdrew from the study within 30 days of enrollment before receiving an LVAD, leaving 74 patients on LVAD support at 12 months.
More patients who received LVAD support achieved the primary composite endpoint than patients who received OMM (39% [33/85] vs. 21% [17/82]; odds ratio: 2.4 [95% confidence interval: 1.2 to 4.8]; p = 0.012) (Table 4). The main reason why fewer OMM patients met the primary endpoint compared with the LVAD group was the use of delayed LVADs in OMM patients.
Thirty-day operative mortality after LVAD implantation was 1%, the same as the mortality rate in the OMM group within 30 days after enrollment. The median hospitalization length of stay after LVAD implantation was 17 days (quartiles 1 to 3: 13 to 22 days). The 12-month as-treated (event-free) survival (freedom from death, urgent heart transplantation, or delayed LVAD) was significantly greater for LVAD versus OMM (80 ± 4% vs. 63 ± 5%; hazard ratio: 1.71 [95% confidence interval: 1.07 to 2.73], p = 0.024) (Figure 2). Using an intention-to-treat analysis, Kaplan-Meier survival (freedom from death) at 12 months was similar in both groups (82 ± 4% vs. 81 ± 4%; p = 0.931) (Figure 3).
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Figure 2.
Survival As-Treated
At 1 year, survival as-treated was significantly higher in LVAD versus OMM patients. Hazard ratio (HR) was calculated for OMM versus LVAD. Abbreviations as in Figure 1.
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Figure 3.
Intention-to-Treat Survival
Intention-to-treat survival was not significantly different between OMM and LVAD patients. HR was calculated for OMM versus LVAD. *One patient received a total artificial heart and was censored alive, then withdrawn from the study. Abbreviations as in Figures 1 and Figure 2.
LVAD patients experienced greater improvements in functional status and quality of life. Compared with 0% before implantation, 77% of LVAD patients improved with NYHA functional class I (25%) or II (52%) at 12 months (Figure 4). Compared with 0% with class I or II symptoms at baseline, 29% of OMM patients alive at 12 months had NYHA functional class II (no class I) symptoms. For LVAD patients, 39 of 71 (55%) improved at least 2 NYHA functional classes compared with 2 of 52 (4%) OMM patients (p < 0.001). Similarly, the average 6MWD improved significantly in LVAD patients (187 m to 263 m; average increase of 75 m; p < 0.001) compared with no significant change in OMM patients (214 to 249 m; average change of 35 m; p = 0.325) (Figure 5).
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Figure 4.
Changes in NYHA Classification
For 1-year survivors on original therapy, significantly more LVAD patients improved to New York Heart Association (NYHA) functional class I or II compared with OMM patients. Patients with missing NYHA classifications were excluded (6 OMM, 3 LVAD). Abbreviations as in Figure 1.
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Figure 5.
Changes in 6MWD
(A) Paired 6-min walk distance (6MWD) measurements at baseline and 12 months for 1-year survivors on original therapy. (B) Average change in 6MWD from baseline to 12 months. Values are mean ± SE. Patients with missing 6MWD were excluded (12 OMM, 8 LVAD). Abbreviations as in Figure 1.
The EQ-5D VAS improved to a significantly greater degree in the LVAD versus OMM groups at 12 months, with an average improvement of 29 points for LVAD compared with 10 points for OMM (p < 0.001) (Figure 6). This outcome was due to LVAD patients starting with worse baseline VAS scores, which increased to levels similar to OMM at 12 months.
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Figure 6.
Changes in Health-Related Quality of Life From the EQ-5D VAS
(A) Paired visual analog scale (VAS) at baseline and 12 months for 1-year survivors on original therapy. (B) Average change in VAS from baseline to 12 months for 1-year survivors on original therapy. Patients with missing VAS were excluded (6 OMM, 8 LVAD). *p < 0.05, ***p < 0.001 for paired changes within study arm. +++p < 0.001 for OMM versus LVAD. EQ-5D = EuroQol; other abbreviations as in Figure 1.
The baseline PHQ-9 scores in paired analysis were higher for LVAD (average: 11 [moderate depression]) compared with OMM patients (average: 7 [mild depression]). Over 12 months, the average values for OMM patients remained the same, compared with LVAD patients who improved from moderate to mild (Figure 7). The composite measures combining survival on original therapy with improvements in NYHA functional class, HRQoL, and depression all showed significantly greater change for LVAD than OMM (Table 5).
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Figure 7.
Changes in Depression From PHQ-9
(A) Paired Patient Health Questionnaire–9 (PHQ-9) scores at baseline and 12 months for 1-year survivors on original therapy. (B) Average change in PHQ-9 score from baseline to 12 months for 1-year survivors on original therapy. Patients with missing PHQ-9 scores were excluded (5 OMM, 7 LVAD). ***p < 0.001 for paired change within study arm. ++p < 0.01, +++p < 0.001 for OMM versus LVAD. Values are mean ± SE. Abbreviations as in Figure 1.
AEs were more frequent in LVAD patients than in OMM patients (Table 6). Bleeding was the primary driver of LVAD AEs; together, surgical and nonsurgical bleeding accounted for 65% of LVAD events. Worsening HF, which accounted for 82% of OMM events, was the primary driver of OMM AEs. Pump thrombus occurred in 6 LVAD patients, 4 requiring pump exchange, with only 1 early event within 90 days of implantation. The median international normalized ratio at 6 and 12 months after LVAD implantation was 2.1 (quartiles 1 to 3: 1.8 to 2.5) and 2.1 (quartiles 1 to 3: 1.7 to 2.5), respectively. At 12 months, 70% of patients were receiving warfarin and antiplatelet therapy (mostly aspirin), 19% were receiving warfarin only, 8% were receiving antiplatelet therapy only, and 3% were on neither warfarin nor antiplatelet agents. The composite AE rate for bleeding, driveline infection, pump thrombosis, stroke, ventricular arrhythmias, and worsening HF was 1.89 EPPY (LVAD) versus 0.83 EPPY (OMM), resulting in a relative risk for OMM versus LVAD of 0.44 (95% confidence interval: 0.35 to 0.56; p < 0.001). Gastrointestinal bleeding was the main bleeding event, accounting for almost two-thirds of all bleeding events, and one-half of the events occurred in 4 patients. Without bleeding, the composite AE rates were similar. More LVAD patients (80%) than OMM patients (62%) had rehospitalizations within 1 year of enrollment, with the reasons shown in Table 7. The leading causes of rehospitalizations were bleeding for LVAD patients and worsening HF for OMM patients. OMM patients who received delayed LVADs had deteriorated from baseline, as evidenced by decreased serum albumin levels, 6MWD, NYHA classification, and INTERMACS profile (Table 8).
The leading causes of death among the 17 patients who died with LVAD support were as follows: sepsis (n = 3 [17.6%]); multiorgan/renal failure (n = 3 [17.6%]); right HF/ventricular tachycardia (n = 2 [11.7%]); thrombus (n = 2 [11.7%]); and 1 (5.8%) each for hemorrhagic stroke, ischemic stroke, bleeding/pleural effusion, respiratory failure, car accident, pulmonary embolism, and unknown. Among the 18 patients in the OMM group, the leading causes of death were progressive HF (n = 13 [72.2%]), with 1 (5.6%) each for sudden cardiac death, chronic obstructive pulmonary disease, sepsis, cancer, and unknown.
Figure 8 displays a summary of the benefits and risks of LVAD therapy versus OMM for patients in the ROADMAP study. LVAD patients were >2 times as likely to reach the primary composite endpoint, and their survival as-treated on original therapy was significantly greater. LVAD patients also had a significantly greater chance of being alive at 12 months with improvements in NYHA functional class, HRQoL, and depression. However, OMM patients experienced less than one-half the AEs as LVAD patients.
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Figure 8.
Risk/Benefit Analysis
Survival, changes in functional capacity, health-related quality of life (HRQol), and depression favor LVAD therapy, but the adverse event rate favors OMM. *Includes patients with baseline VAS <68 (lowest 3 quartiles). †Includes patients with baseline PHQ-9 scores >4 (mild or worse depression severity). LCL = lower confidence limit; OR = odds ratio; UCL = upper confidence limit; other abbreviations as in Figures 1, 2, 6, and 7.
Results
A total of 200 patients were enrolled in the study for LVAD DT support (n = 97) or continuing on OMM (n = 103) (Table 1, Figure 1). Most subjects were men with a median age of 65 years (range 21 to 82 years). Many baseline parameters were characteristic of a patient population with advanced HF and were overall similar between the LVAD and OMM groups. However, patients in the LVAD group compared with the OMM group were more severely ill (NYHA functional class IV: 52% vs. 25%; INTERMACS profile 4: 65% vs. 34%), had lower baseline HRQol, had more severe depression (87% vs. 60% [at least mild depression]), and had lower predicted Seattle Heart Failure Model 12-month survival rates.
(Enlarge Image)
Figure 1.
The ROADMAP Patients at 1 Year
Flow chart depicts outcomes and events within 12 months of enrollment in the ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device [LVAD] and Medical Management) trial. Patients who withdrew from the study or received an elective heart transplant within 1 year were excluded from the primary endpoint analysis. *12 optimal medical management (OMM) patients missing 6-min walk distance data were excluded from the primary endpoint analysis. †8 left ventricular assist device (LVAD) patients missing 6MWD data were excluded from the primary endpoint analysis. ‡Includes 1 elective and 2 urgent transplants.
Patient questionnaires at baseline demonstrated that more LVAD patients reported that they were not satisfied or only slightly satisfied with their quality of life on baseline medical therapy (79%) compared with those who remained on OMM (48%) (Table 2). Significantly more LVAD patients at baseline also reported a perception that they were going to live <1 year (53% vs. 9%). The main patient reasons given for choosing OMM instead of LVAD include not wanting major device surgery, not wanting to depend on a machine, and not feeling sick enough (Table 3). For patients who agreed to LVAD therapy, the main reasons given were anticipated improvement in survival and improvements in quality of life and HF symptoms.
Study Course
A flow chart of all patients and outcomes over the first year is shown in Figure 1. Of the 103 OMM patients, 18 died, 18 received a delayed LVAD at least 1 month after enrollment (including 1 patient receiving a total artificial heart), and 9 patients withdrew from the study before reaching an outcome, leaving 58 patients alive on original OMM therapy at 12 months. The median time from enrollment to delayed LVAD was 138 days (quartiles 1 to 3: 72 to 203 days). For the 97 patients in the LVAD arm, 17 died, 3 received a heart transplant (2 urgent and 1 elective), and 3 withdrew from the study within 30 days of enrollment before receiving an LVAD, leaving 74 patients on LVAD support at 12 months.
Primary Endpoint
More patients who received LVAD support achieved the primary composite endpoint than patients who received OMM (39% [33/85] vs. 21% [17/82]; odds ratio: 2.4 [95% confidence interval: 1.2 to 4.8]; p = 0.012) (Table 4). The main reason why fewer OMM patients met the primary endpoint compared with the LVAD group was the use of delayed LVADs in OMM patients.
Actuarial Survival
Thirty-day operative mortality after LVAD implantation was 1%, the same as the mortality rate in the OMM group within 30 days after enrollment. The median hospitalization length of stay after LVAD implantation was 17 days (quartiles 1 to 3: 13 to 22 days). The 12-month as-treated (event-free) survival (freedom from death, urgent heart transplantation, or delayed LVAD) was significantly greater for LVAD versus OMM (80 ± 4% vs. 63 ± 5%; hazard ratio: 1.71 [95% confidence interval: 1.07 to 2.73], p = 0.024) (Figure 2). Using an intention-to-treat analysis, Kaplan-Meier survival (freedom from death) at 12 months was similar in both groups (82 ± 4% vs. 81 ± 4%; p = 0.931) (Figure 3).
(Enlarge Image)
Figure 2.
Survival As-Treated
At 1 year, survival as-treated was significantly higher in LVAD versus OMM patients. Hazard ratio (HR) was calculated for OMM versus LVAD. Abbreviations as in Figure 1.
(Enlarge Image)
Figure 3.
Intention-to-Treat Survival
Intention-to-treat survival was not significantly different between OMM and LVAD patients. HR was calculated for OMM versus LVAD. *One patient received a total artificial heart and was censored alive, then withdrawn from the study. Abbreviations as in Figures 1 and Figure 2.
Functional Status and Quality of Life
LVAD patients experienced greater improvements in functional status and quality of life. Compared with 0% before implantation, 77% of LVAD patients improved with NYHA functional class I (25%) or II (52%) at 12 months (Figure 4). Compared with 0% with class I or II symptoms at baseline, 29% of OMM patients alive at 12 months had NYHA functional class II (no class I) symptoms. For LVAD patients, 39 of 71 (55%) improved at least 2 NYHA functional classes compared with 2 of 52 (4%) OMM patients (p < 0.001). Similarly, the average 6MWD improved significantly in LVAD patients (187 m to 263 m; average increase of 75 m; p < 0.001) compared with no significant change in OMM patients (214 to 249 m; average change of 35 m; p = 0.325) (Figure 5).
(Enlarge Image)
Figure 4.
Changes in NYHA Classification
For 1-year survivors on original therapy, significantly more LVAD patients improved to New York Heart Association (NYHA) functional class I or II compared with OMM patients. Patients with missing NYHA classifications were excluded (6 OMM, 3 LVAD). Abbreviations as in Figure 1.
(Enlarge Image)
Figure 5.
Changes in 6MWD
(A) Paired 6-min walk distance (6MWD) measurements at baseline and 12 months for 1-year survivors on original therapy. (B) Average change in 6MWD from baseline to 12 months. Values are mean ± SE. Patients with missing 6MWD were excluded (12 OMM, 8 LVAD). Abbreviations as in Figure 1.
The EQ-5D VAS improved to a significantly greater degree in the LVAD versus OMM groups at 12 months, with an average improvement of 29 points for LVAD compared with 10 points for OMM (p < 0.001) (Figure 6). This outcome was due to LVAD patients starting with worse baseline VAS scores, which increased to levels similar to OMM at 12 months.
(Enlarge Image)
Figure 6.
Changes in Health-Related Quality of Life From the EQ-5D VAS
(A) Paired visual analog scale (VAS) at baseline and 12 months for 1-year survivors on original therapy. (B) Average change in VAS from baseline to 12 months for 1-year survivors on original therapy. Patients with missing VAS were excluded (6 OMM, 8 LVAD). *p < 0.05, ***p < 0.001 for paired changes within study arm. +++p < 0.001 for OMM versus LVAD. EQ-5D = EuroQol; other abbreviations as in Figure 1.
The baseline PHQ-9 scores in paired analysis were higher for LVAD (average: 11 [moderate depression]) compared with OMM patients (average: 7 [mild depression]). Over 12 months, the average values for OMM patients remained the same, compared with LVAD patients who improved from moderate to mild (Figure 7). The composite measures combining survival on original therapy with improvements in NYHA functional class, HRQoL, and depression all showed significantly greater change for LVAD than OMM (Table 5).
(Enlarge Image)
Figure 7.
Changes in Depression From PHQ-9
(A) Paired Patient Health Questionnaire–9 (PHQ-9) scores at baseline and 12 months for 1-year survivors on original therapy. (B) Average change in PHQ-9 score from baseline to 12 months for 1-year survivors on original therapy. Patients with missing PHQ-9 scores were excluded (5 OMM, 7 LVAD). ***p < 0.001 for paired change within study arm. ++p < 0.01, +++p < 0.001 for OMM versus LVAD. Values are mean ± SE. Abbreviations as in Figure 1.
Adverse Events
AEs were more frequent in LVAD patients than in OMM patients (Table 6). Bleeding was the primary driver of LVAD AEs; together, surgical and nonsurgical bleeding accounted for 65% of LVAD events. Worsening HF, which accounted for 82% of OMM events, was the primary driver of OMM AEs. Pump thrombus occurred in 6 LVAD patients, 4 requiring pump exchange, with only 1 early event within 90 days of implantation. The median international normalized ratio at 6 and 12 months after LVAD implantation was 2.1 (quartiles 1 to 3: 1.8 to 2.5) and 2.1 (quartiles 1 to 3: 1.7 to 2.5), respectively. At 12 months, 70% of patients were receiving warfarin and antiplatelet therapy (mostly aspirin), 19% were receiving warfarin only, 8% were receiving antiplatelet therapy only, and 3% were on neither warfarin nor antiplatelet agents. The composite AE rate for bleeding, driveline infection, pump thrombosis, stroke, ventricular arrhythmias, and worsening HF was 1.89 EPPY (LVAD) versus 0.83 EPPY (OMM), resulting in a relative risk for OMM versus LVAD of 0.44 (95% confidence interval: 0.35 to 0.56; p < 0.001). Gastrointestinal bleeding was the main bleeding event, accounting for almost two-thirds of all bleeding events, and one-half of the events occurred in 4 patients. Without bleeding, the composite AE rates were similar. More LVAD patients (80%) than OMM patients (62%) had rehospitalizations within 1 year of enrollment, with the reasons shown in Table 7. The leading causes of rehospitalizations were bleeding for LVAD patients and worsening HF for OMM patients. OMM patients who received delayed LVADs had deteriorated from baseline, as evidenced by decreased serum albumin levels, 6MWD, NYHA classification, and INTERMACS profile (Table 8).
The leading causes of death among the 17 patients who died with LVAD support were as follows: sepsis (n = 3 [17.6%]); multiorgan/renal failure (n = 3 [17.6%]); right HF/ventricular tachycardia (n = 2 [11.7%]); thrombus (n = 2 [11.7%]); and 1 (5.8%) each for hemorrhagic stroke, ischemic stroke, bleeding/pleural effusion, respiratory failure, car accident, pulmonary embolism, and unknown. Among the 18 patients in the OMM group, the leading causes of death were progressive HF (n = 13 [72.2%]), with 1 (5.6%) each for sudden cardiac death, chronic obstructive pulmonary disease, sepsis, cancer, and unknown.
Risk/Benefit Analysis
Figure 8 displays a summary of the benefits and risks of LVAD therapy versus OMM for patients in the ROADMAP study. LVAD patients were >2 times as likely to reach the primary composite endpoint, and their survival as-treated on original therapy was significantly greater. LVAD patients also had a significantly greater chance of being alive at 12 months with improvements in NYHA functional class, HRQoL, and depression. However, OMM patients experienced less than one-half the AEs as LVAD patients.
(Enlarge Image)
Figure 8.
Risk/Benefit Analysis
Survival, changes in functional capacity, health-related quality of life (HRQol), and depression favor LVAD therapy, but the adverse event rate favors OMM. *Includes patients with baseline VAS <68 (lowest 3 quartiles). †Includes patients with baseline PHQ-9 scores >4 (mild or worse depression severity). LCL = lower confidence limit; OR = odds ratio; UCL = upper confidence limit; other abbreviations as in Figures 1, 2, 6, and 7.