When Conventional Heart Failure Therapy is not Enough: Angiotensin Receptor Blocker, Direct Renin Inhibitor or Aldosterone Antagonist?

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1 When Conventional Heart Failure Therapy is not Enough: Angiotensin Receptor Blocker, Direct Renin Inhibitor or Aldosterone Antagonist? Sripal Bangalore, MD, MHA, Sunil Kumar, MD, Franz H Messerli, MD, New York University School of Medicine, New York, NY [SB] University of Nebraska, Omaha, NE [SK] St. Luke s-roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, NY [FHM]

2 Disclosure Information Sripal Bangalore: Advisory board- Daiichi Sankyo Sunil Kumar: None Franz H. Messerli: Consulting: Abbott, Novartis, Pfizer, Bayer, Forest, Daiichi-Sankyo, Sanofi, Medtronics and research/grants from Servier, Forest, and Novartis.

I IIa IIb III The addition of an ARB may be considered in persistently symptomatic patients with reduced LVEF who are already being treated with conventional therapy I IIa IIb III Addition of an

3 I IIa IIb III The addition of an ARB may be considered in persistently symptomatic patients with reduced LVEF who are already being treated with conventional therapy I IIa IIb III Addition of an aldosterone antagonist is recommended in selected patients with moderately severe to severe symptoms of HF and reduced LVEF who can be carefully monitored for preserved renal function and normal potassium concentration Jessup et al. Circulation. 2009;119:

be considered in all patients with an LVEF 35% and severe symptomatic HF.

4 I IIa IIb III An ARB is recommended in patients with HF and an LVEF 40% who remain symptomatic despite optimal treatment with an ACEI and b-blocker, unless also taking an aldosterone antagonist I IIa IIb III Addition of a low-dose of an aldosterone antagonist should be considered in all patients with an LVEF 35% and severe symptomatic HF. Aldosterone antagonists reduce hospital admission for worsening HF and increase survival when added to existing therapy, including an ACEI Dickstein et al. European Heart Journal (2008) 29,

5 However, both sets of guideline warn against the combination of dual RAS blockade ( ACEi + ARB) with an aldosterone antagonist

6 Objectives To evaluate the appropriate treatment option in patients with heart failure who remain symptomatic on conventional heart failure therapy (BB, ACEi and Diuretic)

Methods: Search & Eligibility Criteria PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) searches for randomized clinical trials (RCTs) Eligible trials had to fulfill the

7 Methods: Search & Eligibility Criteria PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) searches for randomized clinical trials (RCTs) Eligible trials had to fulfill the following criteria: RCTs comparing the above drug classes Cohort enrolled being heart failure with reduced systolic function on conventional heart failure therapy (including diuretics, beta blockers and angiotensin converting enzyme inhibitors) Follow-up of at least 3 months Enrolling at least 100 patients Able to report the outcomes of interest

8 Study Outcomes Efficacy outcomes Death Cardiovascular (CV) death Heart failure hospitalization Composite of CV death or heart failure hospitalization Safety outcomes Hyperkalemia Renal failure Hypotension

Statistical Analyses Mixed treatment comparison methods were used to compare the different treatment regimens using WinBUGS code Trials were grouped into 4 categories: placebo; ARBs, aldosterone

9 Statistical Analyses Mixed treatment comparison methods were used to compare the different treatment regimens using WinBUGS code Trials were grouped into 4 categories: placebo; ARBs, aldosterone antagonists and DRIs A random-effects Poisson regression model was fitted, taking into account the correlation structure induced by the multi-arm trials The analysis used the rate of efficacy and safety outcomes per 1000 person-years to obtain the log rate ratios of one treatment relative to another treatment Calculation of the probability that each treatment is best (lowest event proportion) was performed using a Bayesian Markov chain Monte Carlo method Minimally informative prior distributions were used for comparisons of treatments, so the findings are close to those obtained with frequentist methods

10 Results: Study Selection Records identified using terms Heart failure, RCT and Human = 5702 Trials excluded for not involving an ARB, DRI or AA=5502 Full-text articles assessed for eligibility (n = 200) Full-text articles excluded due to total number of patients less than 100 or total duration of study less than 3 months (n = 169) Studies included in qualitative synthesis (n = 31) Trials excluded (N=15) Outcome of interest not reported (n=6) Case control studies (n=3) Duplicate publication (n=3) Meta-analysis (n=3) Trial included in the meta-analysis = 16

11 Network of Treatment Comparisons Placebo ARBs AAs DRIs

12 Results: All cause Mortality Placebo (Ref) ARBs vs. Placebo AA vs. Placebo DRI vs. Placebo Rate Ratio (95% CrI) 0.96 (0.80, 1.17) 0.79 (0.66, 0.98) 1.75 (0.67, 4.50) ARBs (Ref) AA vs. ARBs 0.83 (0.63, 1.09) DRI vs. ARBs 1.84 (0.67, 4.67) AA (Ref) DRI vs. AA 2.20 (0.85, 5.81)

13 Results: CV Death Placebo (Ref) ARBs vs. Placebo AA vs. Placebo DRI vs. Placebo Rate Ratio (95% CrI) 0.94 (0.78, 1.07) 0.78 (0.65, 0.93) 1.95 (0.71, 5.69) ARBs (Ref) AA vs. ARBs 0.84 (0.66, 1.08) DRI vs. ARBs 2.10 (0.76, 6.16) AA (Ref) DRI vs. AA 2.48 (0.91, 7.31)

14 Results: HF Hospitalization Placebo (Ref) ARBs vs. Placebo AA vs. Placebo Rate Ratio (95% Cr I) 0.84 (0.68, 1.04) 0.74 (0.55, 0.94) DRI vs. Placebo 1.57 (0.21, 11.33) ARBs (Ref) AA vs. ARBs 0.88 (0.61, 1.21) DRI vs. ARBs 1.86 (0.26, 13.92) AA (Ref) DRI vs. AA 2.14 (0.29, 15.67)

15 Results: CV Death or HF Hospitalization Placebo (Ref) ARBs vs. Placebo AA vs. Placebo Rate Ratio (95% Cr I) 0.93 (0.77, 1.18) 0.73 (0.55, 0.90) DRI vs. Placebo 1.09 (0.57, 2.03) ARBs (Ref) AA vs. ARBs DRI vs. ARBs 0.78 (0.53, 1.04) 1.17 (0.58, 2.26) AA (Ref) DRI vs. AA 1.50 (0.78, 2.99)

16 Results: Hyperkalemia Placebo (Ref) Rate Ratio (95% Cr I) ARBs vs. Placebo 2.38 (1.20, 5.26) AA vs. Placebo 2.10 (1.29, 4.14) DRI vs. Placebo 2.48 (0.86, 7.49) ARBs (Ref) AA vs. ARBs DRI vs. ARBs 0.89 (0.37, 2.35) 1.04 (0.27, 3.76) AA (Ref) DRI vs. AA 1.18 (0.32, 3.81)

Placebo 2.52 (0.62, 11.72) ARBs (Ref) AA vs. ARBs 0.61 (0.18, 2.

17 Results: Renal Failure Placebo (Ref) Rate Ratio (95% Cr I) ARBs vs. Placebo 2.26 (1.14, 6.51) AA vs. Placebo 1.38 (0.67, 3.87) DRI vs. Placebo 2.52 (0.62, 11.72) ARBs (Ref) AA vs. ARBs 0.61 (0.18, 2.11) DRI vs. ARBs 1.08 (0.18, 6.01) AA (Ref) DRI vs. AA 1.79 (0.31, 9.53)

18 Results: Hypotension Placebo (Ref) ARBs vs. Placebo Rate Ratio (95% Cr I) 1.63 (1.30, 2.62) AA vs. Placebo 1.35 (0.78, 2.41) DRI vs. Placebo 1.98 (1.02, 4.07) ARBs (Ref) AA vs. ARBs 0.83 (0.39, 1.43) DRI vs. ARBs 1.20 (0.51, 2.51) AA (Ref) DRI vs. AA 1.48 (0.62, 3.60)

19 Efficacy Outcomes and Probability Best* Treatment Death Rate Rate (95% Cr I) Probability Best CVDeath Rate (95% Cr I) Probability Best HF Hospitalization Rate (95% Cr I) Probability Best CV death or HF Hospitalization Rate (95% Cr I) Probability Best Placebo (25.61, 66.33) 0.7% (19.62, 57.77) 0.2% (77.49, 113.3) 0.2% (141.7, 178.6) 0.1% ARBs (23.74, 65.24) 4.9% (17.95, 55.20) 6.2% (60.56, 102.9) 12.9% (119.2, 190.1) 3.1% AA (19.49, 54.58) 89.1% (15.06, 46.07) 89.9% (50.13, 92.21) 68.8% (85.8, 145.3) 86.9% DRIs (25.59, 191.6) 5.3% (20.91, 215.1) 3.7% (21.77, 965.5) 18.2% (94.5, 316.0) 9.9% *Bayesian Markov chain Monte Carlo method

20 Safety Outcomes and Probability Best* Treatment Hyperkalemia Rate (95% CR I) Probability Best Renal Failure Rate (95% CR I) Probability Best Hypotension Rate (95% CR I) Probability Best Placebo (11.30, 22.10) 94.7% 11.8 (7.30, 17.24) 73.9% (21.12, 33.03) 84.3% ARBs (18.59, 82.73) 0.8% 27.4 (11.78, 69.07) 1.3% (33.39, 66.58) 0.1% AA (20.64, 61.85) 0.3% (7.68, 39.61) 16.8% (20.70, 61.21) 13.5% DRIs (13.08, ) 4.2% 29.9 (6.83, ) 8.0% (26.59, ) 2.1% *Bayesian Markov chain Monte Carlo method

Limitations As in other meta-analyses, given the lack of data in each trial, we did not adjust our analyses for dosage of medications used or with compliance to assigned treatment The percentage of

21 Limitations As in other meta-analyses, given the lack of data in each trial, we did not adjust our analyses for dosage of medications used or with compliance to assigned treatment The percentage of patients on beta-blockers and those who received ICD/CRT was low in a few trials that reported this data Only limited number of trials involving DRI s and it is possible that the results might change when newer trials which larger sample size show any beneficial effect of DRI s

Conclusions (1) When compared with placebo, addition of aldosterone antagonist rather than ARBs or DRIs resulted in a significant reduction of death, cardiovascular death, heart failure

22 Conclusions (1) When compared with placebo, addition of aldosterone antagonist rather than ARBs or DRIs resulted in a significant reduction of death, cardiovascular death, heart failure hospitalization or the composite of cardiovascular death or heart failure hospitalization ARBs were associated with significant increase in the rate of hyperkalemia, renal failure or hypotension Aldosterone antagonists were associated with increase in hyperkalemia and DRI with increase in hypotension

23 Conclusions (2) In patients with heart failure and reduced systolic function who remain symptomatic on conventional heart failure medications including angiotensin converting enzyme inhibitors, the risk benefit ratio favors the addition of aldosterone antagonists over ARBs or DRIs

Heart Rate in Patients with Coronary Artery Disease - the Lower the Better? An Analysis from the Treating to New Targets (TNT) trial

Heart Rate in Patients with Coronary Artery Disease - the Lower the Better? An Analysis from the Treating to New Targets (TNT) trial Sripal Bangalore, MD, MHA, Chuan-Chuan Wun, PhD, David A DeMicco, PharmD,