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Pro-BNP Outpatient Tailored CHF Therapy _PROTECT_ Study

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Pro-BNP Outpatient Tailored CHF Therapy _PROTECT_ Study Powered By Docstoc
					Benefits of Natriuretic Peptide Guided Heart
 Failure Therapy for Patients With Chronic
   Left Ventricular Systolic Dysfunction
       Results of the Pro-BNP Outpatient Tailored
     Chronic Heart Failure Therapy (PROTECT) Study
    James L. Januzzi, Jr, MD, Shafiq U. Rehman, MD, Asim A. Mohammed, MD, Anju
   Bhardwaj, MD, Linda Barajas, RN, Justine Barajas, Han-Na Kim, MD MPH, Aaron L.
Baggish, MD, Rory B. Weiner, MD, Annabel Chen-Tournoux, MD, Jane E. Marshall, RDCS,
Stephanie A. Moore, MD, William D. Carlson, MD, Gregory D. Lewis, MD, Jordan Shin, MD,
Dorothy Sullivan, ANP, Kimberly Parks, DO, Thomas J. Wang, MD, Shawn A. Gregory, MD,
               Shanmugam Uthamalingam, MD, and Marc J. Semigran, MD

                  Heart Center, Massachusetts General Hospital
                             Boston, Massachusetts
       Disclosures

• Dr. Januzzi:

  – Grant support: Roche Diagnostics, Siemens
    Diagnostics, Critical Diagnostics

  – Consulting: Roche Diagnostics, Critical Diagnostics

  – Speaking: Roche Diagnostics, Siemens Diagnostics,
    Ortho Clinical Diagnostics

• No other authors have disclosures to report
         Introduction
• Despite great success in development of therapies for
  chronic heart failure (HF), affected patients nonetheless
  suffer significant morbidity and mortality.
• Standard of care (SOC) management for chronic HF
  includes use of therapies based on symptoms, signs,
  and achievement of a maximal medical program.
• Although such an approach is standard, titration of
  therapies remains sub-optimal, and even when optimal,
  higher risk patients may go unrecognized.
• This has led to greater interest in alternative means to
  monitor patients with HF, in an effort to “guide” therapy.
         Introduction
• Concentrations of amino-terminal pro-B type natriuretic
  peptide (NT-proBNP), are strongly associated with the
  presence and severity of HF, and are markedly
  prognostic in affected patients.

• Values of NT-proBNP often fall in response to therapy
  change, and such a fall in NT-proBNP is associated with
  more favorable outcomes.

• It remains unclear whether “guiding” HF therapy with NT-
  proBNP is beneficial.

   – Clinical trials of guided therapy (with heterogeneous inclusion
     criteria and patient demographics) have returned mixed results.
           Methods
                                      American Heart Journal, 2010




 Investigator-initiated, prospective, randomized controlled trial

          Sponsored in part by Roche Diagnostics, Inc

Clinical Trials.Gov NCT00351390
            Inclusion/Exclusion Criteria

Inclusion Criteria
• Age > 21 years of age
• Left ventricular ejection fraction ≤ 40%
• New York Heart Association class II-IV symptoms
• Hospitalization, ED visit, or outpatient therapy for ADHF within 6 months

Exclusion criteria
• Serum creatinine > 2.5 mg/dl
• Inoperable aortic valve disease
• Life expectancy <1 year due to causes other than HF
• Cardiac transplantation or revascularization expected within 6 months
• Severe obstructive or restrictive pulmonary disease
• PCI or CABG within the previous 3 months
• Subject unable or unwilling to provide written informed consent
              Study Design
   Patient with Class II-IV symptoms, EF  40%, recent HF event

                          Randomization echocardiogram

          Standard of Care                       Standard of Care + NT-proBNP
     Minnesota Living With HF                         Minnesota Living With HF
      Questionnaire quarterly                          Questionnaire quarterly


    Therapy adjusted to achieve              Therapy adjusted to achieve optimal drug
       optimal drug targets                   targets PLUS NT-proBNP  1000 pg/mL
           Visits q3 months                               Visits q3 months
Extra visits as needed for treatment goals     Extra visits as needed for treatment goals



                                 Close-out echocardiogram
                          Total cardiovascular events assessed
                    Endpoints
    • 1 endpoint                                           • 2 endpoints

          – Total cardiovascular                                  – Quality of life
            events*
                                                                  – Changes in echo
                •   Worsening HF†                                   parameters
                •   HF hospitalization
                •   ACS                                                 • LV ejection fraction
                •   Ventricular arrhythmia                              • LVESVi
                •   Cerebral ischemia                                   • LVEDVi
                •   Cardiovascular death
*Assessed using generalized estimating equations
†Requiring  at least 2 from the following: symptoms of congestion or falling cardiac output,
signs of new congestion on exam, use of “bail out” decongestive therapy, or rising NT-proBNP
in the un-blinded arm
PROTECT Study
    Results
  Study flow

151 consented and randomized

Standard of care   Standard of care
plus NT-proBNP          alone
     (N=75)            (N=76)

   6 elective         6 elective
  withdrawals        withdrawals

  75 analyzed        76 analyzed
  0 excluded         0 excluded
      Baseline characteristics
Characteristic                     NT-proBNP (N=75) SOC (N=76) P
Age, years                             63.0 ± 14.5   63.5 ± 13.5   .41
LV ejection fraction (%)                28.0 ± 8.7   25.9 ± 8.3    .52
NYHA Class II or III (%)                65 (85.5)     64 (84.2)    .46
Male gender (%)                         67 (88.2)     61 (81.3)    .24
Caucasian (%)                           65 (85.5)     66 (88.0)    .65
Cause of heart failure
 Ischemic (%)                           40 (53.3)     45 (60.0)
                                                                   .17
 Non-ischemic (%)                       25 (33.3)     18 (24.0)
 Other (%)                              10 (13.3)     12 (16.0)
Past medical history
 Hypertension (%)                       40 (52.6)     39 (52.0)    .94
 Coronary artery disease (%)            42 (55.3)     50 (66.7)    .09
 Myocardial infarction (%)              28 (36.8)     30 (40.0)    .69
 Atrial fibrillation (%)                31 (40.8)     30 (40.0)    .92
 Ventricular tachycardia (%)            23 (30.3)     21 (28.0)    .76
 Obstructive airways disease (%)        15 (19.7)     16 (21.3)    .81
 Diabetes mellitus (%)                  30 (39.5)     32 (42.7)    .19
Implanted devices
  Cardioverter-defibrillator (%)        52 (69.3%)   50 (65.8%)    .70
  Biventricular pacemaker (%)           30 (40.0%)   30 (39.4%)    .68
               HF therapy: Baseline
Medication                                        Baseline
                                   NT-proBNP (N=75) SOC (N=76)     P
ACE Inhibitors (%)                     53 (70.7)       47 (61.8)   .21
Angiotensin receptor blocker (%)       8 (10.7)        15 (19.7)   .11
β blocker (%)                          74 (98.7)       71 (93.4)   .19
Aldosterone antagonist (%)             37 (49.3)       26 (34.2)   .10
Loop Diuretics (%)                     67 (89.3)       71 (93.4)   .27
Thiazide Diuretic (%)                   5 (6.7)         3 (4.0)    .48
Digoxin (%)                            22 (29.3)       25 (32.9)   .89
Hydralazine (%)                         4 (5.3)         4 (5.3)    .89
Nitrates (%)                           8 (10.7)        16 (21.1)   .07
                        Office visits*
          *908 visits overall; mean follow-up 10 ± 3 months

          Median number of visits: NT-proBNP 6.0 vs SOC 5.0; P =.05

              40

              35                                                      SOC
              30                                                      NT-proBNP
% of visits




              25

              20
                                                                      P = .001
              15

              10

              5

              0
                   1-4 visits   5 visits   6-7 visits   ≥8 visits
                                  Visit number
               HF therapy: Follow-up
Medication                                                   Follow-up
                                           NT-proBNP (N=75) SOC (N=76)                  P
ACE Inhibitors (%)                               56 (74.7)              46 (60.5)      .20
Angiotensin receptor blocker (%)                  9 (12.0)              17 (22.4)      .05
β blocker (%)                                    73 (97.3)              73 (96.1)      .56
Aldosterone antagonist (%)                       47 (62.7)              34 (44.7)      .001
Loop Diuretics (%)                               64 (85.3)              73 (96.1)      .05
Thiazide Diuretic (%)                              5 (6.7)                   3 (3.9)   .42
Digoxin (%)                                      23 (30.7)              23 (30.3)      .90
Hydralazine (%)                                    2 (2.7)                   4 (5.3)   .12
Nitrates (%)                                       7 (9.3)              14 (18.4)      .06
Rates of achievement of ≥50% of goal dose were higher in NT-proBNP arm for
ACEi/ARBs (56.5% versus 50.8%) and β blockers (53.4% versus 41.9%).
                HF therapy: Titration
Medication                                      Titration
                                   NT-proBNP (N=75) SOC (N=76)    P
ACE Inhibitors (%)                     +25.4%         +18.1%      .15
Angiotensin receptor blocker (%)        +5.8%         +22.3%      .01
β blocker (%)                          +46.0%         +34.5%      .05
Aldosterone antagonist (%)             +22.7%          +5.8%     <.001
Loop Diuretics (%)                     +23.7%         +25.6%      .65
Thiazide Diuretic (%)*                 -16.7%         -12.5%      .88
Digoxin (%)*                           -10.9%          +2.0%      .78
Hydralazine (%)*                       +27.5%         -50.0%      .20
Nitrates (%)*                          +59.4%          -3.7%      .08
*Limited number of observations
          NT-proBNP Concentrations

               Baseline        Follow-up      P
Overall     2118 [1122-3831] 1321 [554-3197] .02

           By treatment allocation
Treatment     Baseline        Follow-up     P
SOC       1946 [951-3488] 1844 [583-3603] .61
NT-proBNP 2344 [1193-4381] 1125 [369-2537] .01
  P = .40 for SOC baseline versus NT-proBNP baseline
          NT-proBNP Concentrations

                Baseline        Follow-up      P
Overall      2118 [1122-3831] 1321 [554-3197] .02

           By treatment allocation
Treatment     Baseline        Follow-up     P
SOC       1946 [951-3488] 1844 [583-3603] .61
NT-proBNP 2344 [1193-4381] 1125 [369-2537] .01
  P = .03 for SOC follow-up versus NT-proBNP follow-up
           44.3% of NT-proBNP subjects 1000 pg/mL
                             Primary Endpoint
                                        P =.009
                       120                                     SOC
                               100 events                      NT-proBNP
                       100
    Number of events




                       80

                       60
                                               58 events

                       40
                               *Logistic OddsNT-proBNP= 0.44
                       20       (95% CI= .22-.84; P =.019)
                        0
                             Total CV Events
*Adjusted for age, LVEF, NYHA Class, and eGFR
                        Individual Endpoints
                   60                                NB: 0 cerebral ischemia events in either arm



                   50                                                    SOC
Number of events




                                                                         NT-proBNP
                   40
                                           NB: 3 of 4 CV deaths in NT-proBNP arm
                   30                    occurred after elective withdrawal from study


                   20

                         P =.001    P =.002      P =.72        P =.41          P =.52
                   10

                   0
                        Worsening   HF hosp       ACS           VT/VF         CV death
                           HF
                       Kaplan-Meier Analysis
                      1.0
                                                               Log rank P =.03
Event free survival




                      0.8



                      0.6




                      0.4


                                     NT-proBNP (N=75)
                      0.2
                                     Standard-of-care (N=76)

                       0

                            0   73         146      219        292   365

                                     Days from enrollment
                               Age and outcomes

                         1.8     SOC
                         1.6     NT-proBNP
 Mean number of events




                         1.4
                         1.2
                          1
                         0.8
                         0.6
                         0.4
                                   P =.008                  P =.005
                         0.2
                          0
                                Age < 75 years         Age ≥ 75 years
*No interaction between age and NT-proBNP guided care was found (P =.11)
                                Safety

                                                                                                        SOC
                    8                                                                                   NT-proBNP
                    7
% with events




                    6
                    5
                    4
                    3
                    2
                    1           P =.72            P =.70                 P =.32            P =.08         P =.47
                    0
                              Acute                                   Hypo or
                                                  Dizziness                              Hypotension      Syncope
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                                                       H
       Minnesota Living with Heart
       Failure Questionnaire
NT-proBNP patients had larger QOL improvements
   than SOC, and were more likely to have large
 (≥10 point) improvements in their MLWHF scores

Variable        SOC         NT-proBNP        P
Global Scale -5.0 [-18-0] -10.0 [IQR -17-7] .05
≥10 point     38.8%           61.2%        .03
                 Selected echo results

           20
                                                          SOC (N= 56)
           15
                                                          NT-proBNP (N=60)
                 P =.06       P =.01
           10

            5                              LV end-systolic LV end-diastolic
% change




                                            volume index    volume index
            0
                   LVEF         LVEF
            -5   Absolute    Relative 
           -10                                P <.001        P =.008
           -15

           -20
         PROTECT: Limitations
• Small size

• Primary endpoint uses cumulative events

• Effect of NT-proBNP guidance mainly on worsening
  HF and HF hospitalization

• Caregivers and patients un-blinded to NT-proBNP
  results

• Suspension of the study at interim increases the
  risk for Type I error
         PROTECT: Summary
• Against a background of excellent overall medical
  care, addition of NT-proBNP measurement with a
  goal to reduce and maintain values 1000 pg/mL:

  – Was achieved in a large % of subjects

  – Resulted in favorable patterns in medication application

  – Was well-tolerated
         PROTECT: Summary
• NT-proBNP guided care was superior to SOC
  management for the reduction of total
  cardiovascular events.

  – Particular effects on worsening HF and HF
    hospitalization

  – Comparable benefits seen in elderly patients

• Compared to SOC, NT-proBNP guided care was
  associated with more significant improvements in
  both QOL and echo parameters.
        PROTECT: Conclusion


• If duplicated in larger cohorts, therapy guided
  by NT-proBNP concentrations may represent
  a new paradigm for HF care.
Benefits of Natriuretic Peptide Guided Heart
 Failure Therapy for Patients With Chronic
   Left Ventricular Systolic Dysfunction
        Results of the Pro-BNP Outpatient Tailored
      Chronic Heart Failure Therapy (PROTECT) Study
 James L. Januzzi, Jr, MD, Shafiq U. Rehman, MD, Asim A. Mohammed, MD, Anju Bhardwaj, MD,
Linda Barajas, RN, Justine Barajas, Han-Na Kim, MD MPH, Aaron L. Baggish, MD, Rory B. Weiner,
 MD, Annabel Chen-Tournoux, MD, Jane E. Marshall, RDCS, Stephanie A. Moore, MD, William D.
Carlson, MD, Gregory D. Lewis, MD, Jordan Shin, MD, Dorothy Sullivan, ANP, Kimberly Parks, DO,
         Thomas J. Wang, MD, Shawn A. Gregory, MD, Shanmugam Uthamalingam, MD,
                                   and Marc J. Semigran, MD


Slides available at www.cardiosource.com
                   Number of office visits*
                          *908 visits overall; mean follow-up 10 ± 3 months

                   12
Number of visits



                                                             P = .05
                   9




                   6




                   3




                    0
                          SOC               NT-proBNP
                         (N=76)               (N=75)
        Achieved NT-proBNP
 Concentrations of NT-proBNP at the end of the study

                 Treatment arm
Achieved value SOC NT-proBNP
<1000 pg/mL    35.6%    44.3%
<2000 pg/mL    57.5%    68.6%
<3000 pg/mL    69.9%    80.0%
                              Events as a function of NT-proBNP

                         2
                        1.8      P <.001
Mean number of events




                        1.6
                        1.4
                        1.2
                         1
                        0.8
                        0.6
                        0.4
                        0.2
                         0
                              1000 pg/mL     1001-2000 pg/mL   2001-3000 pg/mL   >3000 pg/mL

                                            Achieved NT-proBNP value
                         Mean Number of Events/Patient

                                   P =.03
                                                      SOC
                   1.4     1.3 events                 NT-proBNP
                   1.2
Number of events




                    1
                                        0.77 events
                   0.8

                   0.6

                   0.4

                   0.2

                    0
                     % of Patients with Events

                            P =.04
                60                       SOC
                                         NT-proBNP
                        48.6%
                50
% with events




                40
                                 29.3%
                30

                20

                10

                0
                Safety
Adverse event            NT-proBNP (N=75)   SOC (N=76)   P
Abdominal pain                1.3%             0%        .84
Acute renal failure           5.3%            3.9%       .72
Anemia                        1.3%             0%        .90
Atrial fibrillation           2.7%            3.9%       .67
Cough                         2.7%            1.3%       .41
Diarrhea                      2.7%            1.3%       .65
Dizziness                     6.7%            5.3%       .70
Fever                         1.3%            1.3%       .89
GI bleeding                   1.3%            1.3%       .78
Hyper/hypokalemia             2.7%            1.3%       .32
Hypotension                   5.3%             0%        .08
Respiratory infection         2.7%            5.3%       .25
Syncope                       2.7%            1.3%       .70
             Statistics
•   Differences in characteristics          • Associations between
    between subjects in each arm              treatment strategy and
    were assessed using χ2 test,              treatment-related serious
    Student's t test or Wilcoxon rank         adverse events were
    sum test.                                 examined, after adjustment for
                                              relevant baseline covariates.
•   Comparison of event rates
    between study arms was                  • Parametric and non-parametric
    performed with use of generalized         tests were used to examine
    estimating equations (GEE).               secondary objectives,
                                              including effects of NT-proBNP
     – A logistic β-coefficient, adjusted     guided HF care on QOL, as
       for age, LVEF, NYHA Class, and         well as echo parameters.
       eGFR was calculated for the
       effect of NT-proBNP guidance.        • Interim analysis performed
                                              upon enrollment of 151st
•   Kaplan-Meier analysis performed           subject for assessment of
    to analyze time to first event as a       primary endpoint.
    function of treatment allocation.
             Statistics
•   Differences in characteristics          • Associations between
    between subjects in each arm              treatment strategy and
    were assessed using χ2 test,              treatment-related serious
    Student's t test or Wilcoxon rank         adverse events were
    sum test.                                 examined, after adjustment for
                                              relevant baseline covariates.
•   Comparison of event rates
    between study arms was                  • Parametric and non-parametric
    performed with use of generalized         tests were used to examine
    estimation equations (GEE).               secondary objectives,
                                              including effects of NT-proBNP
     – A logistic β-coefficient, adjusted     guided HF care on QOL, as
       for age, LVEF, NYHA Class, and         well as echo parameters.
       eGFR was calculated for the
       effect of NT-proBNP guidance.        • Interim analysis performed
                                              upon enrollment of 151st
•   Kaplan-Meier analysis performed           subject for assessment of
    to analyze time to first event as a       primary endpoint.
    function of treatment allocation.

				
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