Week 49 – PARADIGM-HF

“Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure”

N Engl J Med. 2014 Sep 11;371(11):993-1004. [free full text]


Background:
Thanks to the CONSENSUS and SOLVD trials, angiotensin-converting enzyme (ACE) inhibitors have been a cornerstone of the treatment of heart failure with reduced ejection fraction (HFrEF) for years. Neprilysin is a neutral endopeptidase that degrades several peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Inhibiting neprilysin increases levels of these substances and thus counteracts the neurohormonal overactivation of heart failure (which would otherwise lead to vasoconstriction, sodium retention, and maladaptive remodeling). Prior experimental data has demonstrated that, in terms of cardiovascular outcomes, neprilysin inhibition with an ARB is superior to ARB monotherapy. However, a clinical trial of concurrent neprilysin-inhibitor and ACE inhibitor therapy resulted in unacceptably high rates of serious angioedema. This study sought to show improved cardiac and mortality outcomes with neprilysin inhibition plus an ARB when compared to enalapril alone.

The study enrolled adults with NYHA class II, III, or IV heart failure, LVEF ≤ 35%, and BNP ≥ 150 or NT-proBNP ≥600. Pertinent exclusion criteria included symptomatic hypotension, SBP < 100mmHg at screening or 95mmHg at randomization, eGFR < 30 or decrease in eGFR by 25% between screening and randomization, K+ > 5.2, or history of angioedema/side effects to ACE inhibition or ARBs. Patients were randomized to treatment with either sacubitril/valsartan 200mg BID or to enalapril 10mg BID. (Screened patients were initially given sacubitril/valsartan followed by enalapril in single blinded run-in phases in order to ensure similar tolerance of the drugs prior to randomization.) The primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure. Selected secondary outcomes included: 1) change from baseline in the clinical summary score of the Kansas City Cardiomyopathy Questionnaire (KCCQ), 2) time to new-onset atrial fibrillation, and 3) time to first occurrence of decline in renal function.

 

Results:
4187 patients were randomized to the sacubitril/valsartan group, and 4212 were randomized to the enalapril group.

The primary endpoint (composite death due to cardiovascular causes or first hospitalization for HF) occurred in 914 patients (21.8%) in the sacubitril/valsartan group and 1117 patients (26.5%) in the enalapril group (p < 0.001; NNT = 21). Death due to cardiovascular causes occurred 558 times in the sacubitril/valsartan group and 693 times in the enalapril group (13.3% vs. 16.5%, p < 0.001; NNT = 31). Hospitalization for heart failure occurred (at least once) 537 times in the sacubitril/valsartan group and 658 times in the enalapril group (12.8% vs. 15.6%, p < 0.001; NNT = 36).

Regarding secondary outcomes, the mean change in KCCQ score was a reduction of 2.99 points (i.e. a worsening of symptoms) in the sacubitril/valsartan group versus a reduction of 4.63 points in the enalapril group (p = 0.001). There was no significant group difference in time to new-onset atrial fibrillation or time to diminished renal function.

Regarding safety outcomes, patients in the sacubitril/valsartan group were more likely to have symptomatic hypotension compared to patients in the enalapril group (14.0% vs. 9.2%; p < 0.001; NNH = 21). However, patients in the enalapril group were more likely to have cough, serum creatinine ≥ 2.5, or potassium ≥6.0 compared to sacubitril/valsartan (p value varies, all significant). There was no group difference in rates of angioedema (p = 0.13).

Implication/Discussion:
In patients with HFrEF, inhibition of both angiotensin II and neprilysin with sacubitril/valsartan significantly reduced the risk of cardiovascular death or hospitalization for heart failure when compared to treatment with enalapril alone.

This study had several strengths. The treatment with sacubitril/valsartan was compared to treatment with a dose of enalapril that had previously been shown to reduce mortality when compared with placebo. Furthermore, the study used a run-in phase to ensure that patients could tolerate an enalapril dose that had previously been shown to reduce mortality. Finally, more patients in the enalapril group than in the sacubitril/valsartan group stopped the study drug due to adverse effects (12.3% vs. 10.7%, p = 0.03).

This study ushered in a new era in heart failure management and added a new medication class – Angiotensin Receptor-Neprilysin Inhibitors or ARNIs – to the arsenal of available heart failure drugs. Entresto (sacubitril/valsartan), the ARNI posterchild, has been advertised widely over the past several years. However, clinical use so far has been lower than expected (see http://www.cardiobrief.org/2017/12/05/after-slow-start-entresto-is-poised-for-takeoff/). Novartis, Entresto’s drug maker, is currently sponsoring PARAGON-HF, a trial of Entresto in patients with heart failure with preserved ejection fraction (HFpEF).

The 2017 ACC/AHA update to the guidelines for management of symptomatic HFrEF states that primary inhibition of the renin-angiotensin system with an ARNI in conjunction with evidence-based beta blockade and aldosterone antagonism is a Class I recommendation (Level B evidence). However, it does not favor this regimen over the Level-A-evidence regimens of an ARB or ACE inhibitor substituted for the ARNI. Yet the new guidelines also state that patients who have chronic symptomatic HFrEF of NYHA class II or III and tolerate an ACE inhibitor or ARB should substitute an ARNI for the ACE inhibitor or ARB in order to further reduce morbidity and mortality (Class I recommendation, level B evidence). See pages 15 and 17 here to read the details.

Bottom line:
Among patients with symptomatic HFrEF, treatment with an ARNI reduces cardiovascular mortality and HF hospitalizations when compared to treatment with enalapril. Due to this study’s impact, the use of ARNIs is now a Class I recommendation by the 2017 ACC/AHA guidelines for the treatment of HFrEF. Despite its higher cost, the use of sacubitril/valsartan appears to be cost-effective in terms of QALYs gained.

Further Reading/References:
1. PARADIGM-HF @ Wiki Journal Club
2. PARADIGM-HF @ 2 Minute Medicine
3. ACC/AHA 2017 Focused Update for Guideline Management of Heart Failure
4. CardioBrief, “After Slow Start Entresto Is Poised For Takeoff.”
5. PARAGON-HF @ ClinicalTrials.gov
6. McMurray et al., “Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction.” Heart, 2017.

Summary by Patrick Miller, MD

Week 43 – FREEDOM

“Strategies for Multivessel Revascularization in Patients with Diabetes”

by the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) Trial investigators

N Engl J Med. 2012 Dec 20;367(25):2375-84. [free full text]

Previous studies, such as the 1996 BARI trial), have demonstrated that patients who have multivessel coronary artery disease (CAD) and diabetes mellitus (DM) and who received coronary artery bypass grafting (CABG) surgery lived longer than patients undergoing balloon angioplasty. However, since that publication, percutaneous coronary intervention (PCI) technology advanced significantly. Prior to the publication of FREEDOM in 2012, there had only been small, underpowered studies comparing PCI with drug-eluting stent (DES) to CABG. FREEDOM was powered appropriately to discover superiority of revascularization strategy (PCI with DES vs. CABG) in patients with DM and multivessel CAD.

Population:

Inclusion criteria:

      • 18 years or older
      • Diabetes mellitus – defined by American Diabetes Association
      • Multivessel Coronary Artery Disease
        • > 70% stenosis (angiographically confirmed)
        • 2 or more epicardial vessels
        • 2 or more coronary-artery territories

Selected exclusion criteria:

      • NYHA Class III-IV heart failure
      • Prior CABG, valve surgery, or PCI (< 6 months)
      • Prior significant bleed (< 6 months)
      • Left main stenosis ≥ 50%

 

Design:
Patients meeting criteria were assigned 1:1 into PCI with first-generation paclitaxel-eluting stent (51%) or sirolimus-eluting stent (43%) versus CABG. The PCI group was placed on aspirin and clopidogrel for dual antiplatelet therapy (DAPT) for at least 12 months. For the CABG group, arterial revascularization was encouraged. The mean SYNTAX score (tool used to score complexity of CAD) was 26.2 and did not significantly differ between groups. Guideline-driven targets for lowering medical risk factors were used: LDL <70, BP <130/80, HgbA1c <7. Minimum follow-up was 2 years.


Outcomes:

Primary: Composite of death from any cause, non-fatal myocardial infarction (MI), and non-fatal stroke

Secondary

      1. Rate of major adverse cardiovascular and cerebrovascular events at 30 days and 12 months
      2. Repeat revascularization
      3. Annual all-cause mortality
      4. Annual cardiovascular mortality


Results:
953 patients and 947 patients were randomized into the PCI and CABG groups, respectively. At 5 years, the primary outcome (combined death, MI, or stroke) occurred in 200 of the PCI group and 146 of the CABG group (26.6% vs 18.7%, p = 0.005). The curves started diverging at 2 years. All-cause mortality was higher in the PCI group versus the CABG group (16.3% vs 10.9%, p = 0.049). Regarding secondary outcomes, 13.9% of patients in the PCI group had a repeat MI versus 6.0% in the CABG group (p < 0.001). There were fewer strokes in the PCI group than in the CABG group (2.4% vs 5.2%, p = 0.03). There was no statistically significant difference between study groups regarding cardiovascular death (10.9% vs 6.8%, p = 0.12).

At 5 years, the analysis of outcomes according to category of SYNTAX score (≤ 22, 23 to 32, ≥ 33) showed no significant subgroup interaction (p = 0.58).

Regarding safety, major bleeding between the two groups at 30 days was 0.02% for PCI vs 0.04% for CABG (p = 0.13). The incidence of acute renal failure requiring hemodialysis was observed in one patient in the PCI group and eight patients in the CABG group (p = 0.02)

Implication/Discussion:
The BARI Trial (1996) was the first trial to show that patients with DM and multivessel CAD derive mortality benefit from bypass grafting over PCI with balloon angioplasty. Furthermore, the BARI 2D (2009) trial demonstrated this benefit of bypass grafting over PCI with bare metal stents (BMS). At the time of the FREEDOM Trial, there had not been a randomized comparison of CABG versus PCI with newer technology and first-generation paclitaxel/sirolimus DES. In this study, CABG showed a 5.3% absolute reduction in all-cause mortality over PCI as well decreased rates of MI and repeat revascularization. CABG was associated with a mild absolute increase in stroke (2.8%). However, this mild increased stroke risk is consistent with most other comparative trials of the two treatment strategies. There was no statistical difference in major bleeding between the two groups.

CABG is likely better than PCI for various reasons. For one, diabetic arteries are affected diffusely and tend to have more extensive atherosclerotic disease compared to those without diabetes, so the likelihood of successful PCI alone is low. Many suspected that with advancement in PCI (i.e. DES) that the BARI data would become irrelevant. However, CABG continued to show benefit despite the technological advancements of drug-eluting stents and PCI. Improvement in surgical technique as well as the use of arterial revascularization (i.e. internal mammary artery) helped maintain superior outcomes with CABG compared to PCI.

The study was limited by the fact that due to low numbers, the subgroup analysis (i.e. SYNTAX scores) was not appropriately powered for statistical significance. Further, the study was not blinded, and patients may have been treated differently on the basis of their surgical procedure. Also, there was variability of STYNAX scores between the study groups, but this circumstance was thought to reflect real world heterogeneity.

Bottom Line:
CABG was superior to PCI with DES in patients with DM and multivessel CAD in that it significantly reduced rates of death and MI despite a small increased risk of stroke.

Further Reading/References:
1. BARI Trial @ NEJM
2. BARI 2D Trial @ NEJM
3. ACCF/AHA 2011 Guideline for Coronary Artery Bypass Graft Surgery
4. FREEDOM @ Wiki Journal Club
5. FREEDOM @ 2 Minute Medicine
5. FREEDOM @ Visualmed

Summary by Patrick Miller, MD.

Image Credit: Jerry Hecht, US Public Domain, via Wikimedia Commons

Week 36 – HAS-BLED

“A Novel User-Friendly Score (HAS-BLED) To Assess 1-Year Risk of Major Bleeding in Patients with Atrial Fibrillation”

Chest. 2010 Nov;138(5):1093-100 [free full text]

Atrial fibrillation (AF) is a well-known risk factor for ischemic stroke. Stroke risk is further increased by individual comorbidities, such as CHF, HTN, and DM, and can be stratified with scores, such as CHADS2 and CHA2DS2VASC. Patients with intermediate stroke risk are recommended to be treated with oral anticoagulation (OAC). However, stroke risk is often also closely related to bleeding risk, and the benefits of anticoagulation for stroke need to be weighed against the added risk of bleeding. At the time of this study, there were no validated and user-friendly bleeding risk-stratification schemes. This study aimed to develop a practical risk score to estimate the 1-year risk of major bleeding (as defined in the study) in a contemporary, real world cohort of patients with AF.

The study enrolled adults with an EKG or Holter-proven diagnosis of AF. (Patients with mitral valve stenosis or previous valvular surgery were excluded.) No experiment was performed in this retrospective cohort study.

In a derivation cohort, the authors retrospectively performed univariate analyses to identify a range of clinical features associated with major bleeding (p < 0.10). Based on systematic reviews, they added additional risk factors for major bleeding. Ultimately, what resulted was a list of comprehensive risk factors deemed HAS-BLED:

H – Hypertension (> 160 mmHg systolic)
A – Abnormal renal (HD, transplant, Cr > 2.26 mg/dL) and liver function (cirrhosis, bilirubin > 2x normal w/ AST/ALT/ALP > 3x normal) – 1 pt each for abnormal renal or liver function
S – Stroke

B – Bleeding (prior major bleed or predisposition to bleed)
L – Labile INRs (time in therapeutic range < 60%)
E – Elderly (age > 65)
D – Drugs (i.e. ASA, clopidogrel, NSAIDs) or alcohol use (> 8 units per week) concomitantly – 1 pt each for use of either

Each risk factor was equivalent to one point. The HAS-BLED score was then compared to the HEMORR2HAGES scheme [https://www.mdcalc.com/hemorr2hages-score-major-bleeding-risk], a prior tool for estimating bleeding risk.

Outcomes:

      • incidence of major bleeding within 1 year, overall
      • bleeds per 100 patient-years, by HAS-BLED score
      • c-statistic for the HAS-BLED score in predicting the risk of bleeding

Definitions:

      • major bleeding = bleeding causing hospitalization, Hgb drop >2 g/L, or requiring blood transfusion, that was not a hemorrhagic stroke
      • hemorrhagic stroke = focal neurologic deficit of sudden onset, diagnosed by a neurologist, lasting >24h and caused by bleeding

Results:
3,456 patients with AF without mitral valve stenosis or valve surgery who completed their 1-year follow-up were analyzed retrospectively. 64.8% (2242) of these patients were on OAC (12.8% of whom on concurrent antiplatelet therapy), 24% (828) were on antiplatelet therapy alone, and 10.2% (352) received no antithrombotic therapy. 1.5% (53) of patients experienced a major bleed during the first year, with 17% (9) of these patients sustaining intracerebral hemorrhage.

HAS-BLED Score       Bleeds per 100-patient years
0                                        1.13
1                                         1.02
2                                        1.88
3                                        3.74
4                                        8.70
5                                        12.50
6*                                     0.0                   *(n = 2 patients at risk, neither bled)

Patients were given a HAS-BLED score and a HEMORR2HAGES score. C-statistics were then used to determine the predictive accuracy of each model overall as well as within patient subgroups (OAC alone, OAC + antiplatelet, antiplatelet alone, no antithrombotic therapy).

C statistics for HAS-BLED were as follows: for overall cohort, 0.72 (95%CI 0.65-0.79); for OAC alone, 0.69 (95%CI 0.59-0.80); for OAC + antiplatelet, 0.78 (95%CI 0.65-0.91); for antiplatelet alone, 0.91 (95%CI 0.83-1.00); and for those on no antithrombotic therapy, 0.85 (95%CI 0.00-1.00).

C statistics for HEMORR2HAGES were as follows: for overall cohort, 0.66 (95%CI 0.57-0.74); for OAC alone, 0.64 (95%CI 0.53-0.75); for OAC + antiplatelet, 0.83 (95%CI 0.74-0.91); for antiplatelet alone, 0.83 (95%CI 0.68-0.98); and for those without antithrombotic therapy, 0.81 (95%CI 0.00-1.00).

Implication/Discussion:
This study helped to establish a practical and user-friendly assessment of bleeding risk in AF. HAS-BLED is superior to its predecessor HEMORR2HAGES in that it has an easier-to-remember acronym and is quicker and simpler to perform. All of its risk factors are readily available from the clinical history or are routinely tested. Both stratification tools had a broadly similar c-statistics for the overall cohort – 0.72 for HAS-BLED versus 0.66 for HEMORR2HAGES respectively. However, HAS-BLED was particularly useful when looking at antiplatelet therapy alone or no antithrombotic therapy at all (0.91 and 0.85, respectively).

This study is useful because it provides evidence-based, easily-calculable, and actionable risk stratification in assessing bleeding risk in AF. In prior studies, such as ACTIVE-A (ASA + clopidogrel versus ASA alone for patients with AF deemed unsuitable for OAC), almost half of all patients (n= ~3500) were given a classification of “unsuitable for OAC,” which was based solely on physician clinical judgement alone without a predefined objective scoring. Now, physicians have an objective way to assess bleed risk rather than “gut feeling” or wanting to avoid iatrogenic insult.

The RE-LY trial used the HAS-BLED score to decide which patients with AF should get the standard dabigatran dose (150mg BID) versus a lower dose (110mg BID) for anticoagulation. This risk-stratified dosing resulted in a significant reduction in major bleeding compared with warfarin and maintained a similar reduction in stroke risk.

Furthermore, the HAS-BLED score could allow the physician to be more confident when deciding which patients may be appropriate for referral for a left atrial appendage occlusion device (e.g. Watchman).

Limitations:
The study had a limited number of major bleeds and a short follow-up period, and thus it is possible that other important risk factors for bleeding were not identified. Also, there were large numbers of patients lost to 1-year follow-up. These patients were likely to have had more comorbidities and may have transferred to nursing homes or even have died – which may have led to an underestimate of bleeding rates. Furthermore, the study had a modest number of very elderly patients (i.e. 75-84 and ≥85), who are likely to represent the greatest bleeding risk.

Bottom Line:
HAS-BLED provides an easy, practical tool to assess the individual bleeding risk of patients with AF. Oral anticoagulation should be considered for scores of 3 or less. HAS-BLED scores are ≥4, it is reasonable to think about alternatives to oral anticoagulation.

Further Reading/References:
1. HAS-BLED @ 2 Minute Medicine
2. ACTIVE-A trial
3. RE-LY trial:
4. RE-LY @ Wiki Journal Club
5. HAS-BLED Calculator
6. HEMORR2HAGES Calculator
7. CHADS2 Calculator
8. CHA2DS2VASC Calculator
9. Watchman (for Healthcare Professionals)

Summary by Patrick Miller, MD

Image Credit: CardioNetworks, CC BY-SA 3.0, via Wikimedia Commons

Week 48 – HAS-BLED

“A Novel User-Friendly Score (HAS-BLED) To Assess 1-Year Risk of Major Bleeding in Patients with Atrial Fibrillation”

Chest. 2010 Nov;138(5):1093-100. [free full text]

Atrial fibrillation (AF) is a well-known risk factor for ischemic stroke. Stroke risk is further increased by individual comorbidities such as CHF, HTN, and DM and can be stratified with scores such as CHADS2 and CHA2DS2VASC. The recommendation for patients with intermediate stroke risk is treatment with oral anticoagulation (OAC). However, stroke risk is often closely related to bleeding risk, and the benefits of anticoagulation for stroke need to be weighed against the added risk of bleeding. At the time of this study, there were no validated and user-friendly bleeding risk-stratification schemes. This study aimed to develop a practical risk score to estimate the 1-year risk of major bleeding (as defined in the study) in a contemporary, real-world cohort of patients with AF.

Population: adults with EKG or Holter-proven diagnosis of AF
Exclusion criteria: mitral valve stenosis, valvular surgery

(Patients were identified from the prospectively developed database of the multi-center Euro Heart Survey on AF. Among 5,272 patients with AF, 3,456 were free of mitral valve stenosis or valve surgery and completed their 1-year follow-up assessment.)

No experiment was performed in this retrospective cohort study.

In a derivation cohort, the authors retrospectively performed univariate analyses to identify a range of clinical features associated with major bleeding (p < 0.10). Based on systematic reviews, they added additional risk factors for major bleeding. Ultimately, the result was a list of comprehensive risk factors that make up the acronym HAS-BLED:

H – Hypertension (> 160 mmHg systolic)
A – Abnormal renal (HD, transplant, Cr > 2.26 mg/dL) and liver function (cirrhosis, bilirubin >2x normal w/ AST/ALT/ALP > 3x normal) – 1 pt each for abnormal renal or liver function
S – Stroke

B – Bleeding (prior major bleed or predisposition to bleed)
L – Labile INRs (time in therapeutic range < 60%)
E – Elderly (age > 65)
D – Drugs (i.e. ASA, clopidogrel, NSAIDs) or alcohol use (> 8 units per week) concomitantly – 1 pt each for use of either

Each risk factor represents one point each. The HAS-BLED score was then compared to the HEMORR2HAGES scheme, a previously developed tool for estimating bleeding risk.

Outcomes:

  • incidence of major bleeding within 1 year
  • bleeds per 100 patient-years, stratified by HAS-BLED score
  • c-statistic for the HAS-BLED score in predicting the risk of bleeding

Definitions:

  • major bleeding: bleeding causing hospitalization, Hgb drop >2 g/L, or bleeding requiring blood transfusion (excluded hemorrhagic stroke)
  • hemorrhagic stroke: focal neurologic deficit of sudden onset that is diagnosed by a neurologist, lasting > 24h, and caused by bleeding

Results:
3,456 AF patients (without mitral valve stenosis or valve surgery) who completed their 1-year follow-up were analyzed retrospectively. 64.8% (2242) of these patients were on OAC (with 12.8% (286) of this subset on concurrent antiplatelet therapy), 24% (828) were on antiplatelet therapy alone, and 10.2% (352) received no antithrombotic therapy. 1.5% (53) of patients experienced a major bleed during the first year. 17% (9) of these patients sustained intracerebral hemorrhage.

HAS-BLED Score       Bleeds per 100-patient years
0                                        1.13
1                                         1.02
2                                        1.88
3                                        3.74
4                                        8.70
5                                        12.50
6*                                     0.0                   *(n = 2 patients at risk, neither bled)

Patients were given a HAS-BLED score and a HEMORR2HAGES score. C-statistics were then used to determine the predictive accuracy of each model overall as well as within patient subgroups (OAC alone, OAC + antiplatelet, antiplatelet alone, and no antithrombotic therapy).

C statistics for HAS-BLED:
For overall cohort, 0.72 (95% CI 0.65-0.79); for OAC alone, 0.69 (95% CI 0.59-0.80); for OAC + antiplatelet, 0.78 (95% CI 0.65-0.91); for antiplatelet alone, 0.91 (95% CI 0.83-1.00); and for those on no antithrombotic therapy, 0.85 (95% CI 0.00-1.00).

C statistics for HEMORR2HAGES:
For overall cohort, 0.66 (95% CI 0.57-0.74); for OAC alone, 0.64 (95% CI 0.53-0.75); for OAC + antiplatelet, 0.83 (95% CI 0.74-0.91); for antiplatelet alone, 0.83 (95% CI 0.68-0.98); and for those on no antithrombotic therapy, 0.81 (95% CI 0.00-1.00).

Implication/Discussion:
This study helped to establish a practical and user-friendly assessment of bleeding risk in AF. HAS-BLED is superior to its predecessor HEMORR2HAGES because the acronym is easier to remember, the assessment is quicker and simpler to perform, and all risk factors are readily available from the clinical history or routine testing. Both stratification tools had (grossly) similar c-statistics for the overall cohort – 0.72 for HAS-BLED versus 0.66 for HEMORR2HAGES. However, HAS-BLED was particularly useful when looking at antiplatelet therapy alone or no antithrombotic therapy at all (0.91 and 0.85, respectively).

This study is useful because it provides evidence-based, easily calculable, and actionable risk stratification in the assessment of bleeding risk in AF. In prior studies, such as ACTIVE-A (ASA + clopidogrel versus ASA alone for patients with AF deemed unsuitable for OAC), almost half of all patients (n= ~3500) were given a classification of “unsuitable for OAC,” which was based solely on physicians’ clinical judgement without a predefined objective scoring. Now, physicians have an objective way to assess bleed risk rather than “gut feeling” or wanting to avoid iatrogenic insult.

The RE-LY trial used the HAS-BLED score to decide which patients with AF should get the standard dabigatran dose (150mg BID) rather than a lower dose (110mg BID) for anticoagulation. This risk-stratified dosing resulted in a significant reduction in major bleeding compared with warfarin but maintained a similar reduction in stroke risk.

Furthermore, the HAS-BLED score could allow the physician to be more confident when deciding which patients may be appropriate for referral for a left atrial appendage occlusion device (e.g. Watchman).

Limitations:
The study had a limited number of major bleeds and a short follow-up period, and thus it is possible that other important risk factors for bleeding were not identified. Also, there were large numbers of patients lost to 1-year follow-up. These patients likely had more comorbidities and may have transferred to nursing homes or even died. Their loss to follow-up and thus exclusion from this retrospective study may have led to an underestimate of true bleeding rates. Furthermore, generalizability is limited by the modest number of very elderly patients (i.e. 75-84 and ≥85), who likely represent the greatest bleeding risk. Finally, this study did not specify what proportion of its patients were on warfarin for their OAC, but given that dabigatran, rivaroxaban, and apixaban were not yet approved for use in Europe (2008, 2008, and 2011, respectively) for the majority of the study, we can assume most patients were on warfarin. Thus the generalizability of HAS-BLED risk stratification to the DOACs is limited.

Bottom Line:
HAS-BLED provides an easy, practical tool to assess the individual bleeding risk of patients with AF. Oral anticoagulation should be considered for scores of 3 or less. If HAS-BLED scores are ≥4, it is reasonable to think about alternatives to oral anticoagulation.

Further Reading/References:
1. 2 Minute Medicine
2. ACTIVE-A trial
3. RE-LY trial
4. RE-LY @ Wiki Journal Club
5. HAS-BLED Calculator
6. HEMORR2HAGES Calculator
7. Watchman (for Healthcare Professionals)

Summary by Patrick Miller, MD

Week 37 – PARADIGM-HF

“Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure”

by the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) investigators

N Engl J Med. 2014 Sep 11;371(11):993-1004. [free full text]

Thanks to the CONSENSUS and SOLVD trials, angiotensin-converting enzyme (ACE) inhibitors have been a cornerstone of the treatment of heart failure with reduced ejection fraction (HFrEF) for years.

Neprilysin is a neutral endopeptidase that degrades several peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Inhibiting neprilysin increases levels of these substances and thus counteracts the neurohormonal overactivation of heart failure (which would otherwise lead to vasoconstriction, sodium retention, and maladaptive remodeling). Prior experimental data has demonstrated that, in terms of cardiovascular outcomes, neprilysin inhibition with an ARB is superior to ARB monotherapy. However, a clinical trial of concurrent neprilysin-inhibitor and ACE inhibitor therapy resulted in unacceptably high rates of serious angioedema. This study sought to show improved cardiac and mortality outcomes with neprilysin inhibition plus an ARB when compared to enalapril alone.

Population:
Inclusion Criteria: ≥18 y/o; NYHA class II, III, or IV; LVEF ≤ 35%; BNP ≥ 150 or NT-proBNP ≥600

Exclusion Criteria: Symptomatic hypotension, SBP < 100mmHg at screening or 95mmHg at randomization, eGFR < 30, or decrease in eGFR by 25% between screening and randomization, K+ > 5.2, or history of angioedema/side effects to ACE inhibition or ARBs

Intervention: sacubitril/valsartan 200mg BID

Comparison: enalapril 10mg BID

Trial design notes: Screened patients were initially given sacubitril/valsartan, followed by enalapril in single blinded run-in phases, in order to ensure similar tolerance of the drugs prior to randomization. Subsequently, patients who tolerated both drugs were randomized in a double-blind manner to treatment with one of the drugs. 

Outcome:
Primary – composite of death from cardiovascular causes or first hospitalization for heart failure

Secondary


Results:
4187 patients were randomized to the sacubitril/valsartan group, and 4212 were randomized to the enalapril group.

The primary endpoint (composite death due to cardiovascular causes or first hospitalization for HF) occurred in 914 patients (21.8%) in the sacubitril/valsartan group and 1117 patients (26.5%) in the enalapril group (p < 0.001; NNT = 21). Death due to cardiovascular causes occurred 558 times in the sacubitril/valsartan group and 693 times in the enalapril group (13.3% vs. 16.5%, p < 0.001; NNT = 31). Hospitalization for heart failure occurred (at least once) 537 times in the sacubitril/valsartan group and 658 times in the enalapril group (12.8% vs. 15.6%, p <0.001; NNT = 36).

Regarding secondary outcomes, the mean change in KCCQ score was a reduction of 2.99 points (i.e. a worsening of symptoms) in the sacubitril/valsartan group, versus a reduction of 4.63 points in the enalapril group (p = 0.001). There was no significant group difference in time to new-onset atrial fibrillation or time to diminished renal function.

Regarding safety outcomes, patients in the sacubitril/valsartan group were more likely to have symptomatic hypotension compared to patients in the enalapril group (14.0% vs. 9.2%; p <0.001; NNH = 21). However, patients in the enalapril group were more likely to have cough, serum creatinine ≥2.5, or potassium ≥6.0 compared to sacubitril/valsartan (p value varies, all significant). There was no group difference in rates of angioedema (p = 0.13).


Implication/Discussion:
In patients with HFrEF, inhibition of both angiotensin II and neprilysin with sacubitril/valsartan significantly reduced the risk of cardiovascular death or hospitalization for heart failure when compared to treatment with enalapril alone.

This study had several strengths. The treatment with sacubitril/valsartan was compared to treatment with a dose of enalapril that had previously been shown to reduce mortality when compared with placebo. Furthermore, the study used a run-in phase to ensure that patients could tolerate an enalapril dose that had previously been shown to reduce mortality. Finally, more patients in the enalapril group than in the sacubitril/valsartan group stopped the study drug due to adverse effects (12.3% vs. 10.7%, p=0.03).

This study ushered in a new era in heart failure management and added a new medication class – Angiotensin Receptor-Neprilysin Inhibitors or ARNIs – to the arsenal of available heart failure drugs. Entresto (sacubitril/valsartan), the ARNI posterchild, has been advertised widely over the past several years. However, clinical use so far has been lower than expected. Novartis, Entresto’s drug maker, is currently sponsoring PARAGON-HF, a trial of Entresto in patients with heart failure with preserved ejection fraction (HFpEF).

The 2017 ACC/AHA update to the guidelines for management of symptomatic HFrEF states that primary inhibition of the renin-angiotensin system with an ARNI in conjunction with evidence-based beta blockade and aldosterone antagonism is a Class I recommendation (Level B evidence). However, it does not favor this regimen over the Level-A-evidence regimens of an ARB or ACE inhibitor substituted for the ARNI. Yet the new guidelines also state that patients who have chronic symptomatic HFrEF of NYHA class II or III and tolerate an ACE inhibitor or ARB should substitute an ARNI for the ACE inhibitor or ARB in order to further reduce morbidity and mortality (Class I recommendation, level B evidence). See pages 15 and 17 here to read the details.

Bottom line: Among patients with symptomatic HFrEF, treatment with an ARNI reduces cardiovascular mortality and HF hospitalizations when compared to treatment with enalapril. Due to this study’s impact, the use of ARNIs is now a Class I recommendation by the 2017 ACC/AHA guidelines for the treatment of HFrEF. Despite its higher cost, the use of sacubitril/valsartan appears to be cost-effective in terms of QALYs gained.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. ACC/AHA 2017 Focused Update for Guideline Management of Heart Failure
4. CardioBrief, “After Slow Start Entresto Is Poised For Takeoff.”
5. PARAGON-HF @ ClinicalTrials.gov
6. McMurray et al., “Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction.” Heart, 2017.

Summary by Patrick Miller, MD

Week 34 – PLATO

“Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes”

by The Study of Platelet Inhibition and Patient Outcomes (PLATO) investigators

N Engl J Med. 2009 Sep 10;361(11):1045-57. [free full text]

In patients with acute coronary syndrome (ACS), with or without ST-segment elevation, clinical practice guidelines recommend dual antiplatelet therapy with aspirin plus one of either clopidogrel, prasugrel, or ticagrelor to reduce risk of thrombosis. The 2009 PLATO trial was designed to determine whether ticagrelor was superior to clopidogrel for the prevention of vascular events and death in patients presenting with ACS as well as whether this potential benefit came with an increased risk of major bleeding events.

Population:
Patients hospitalized for ACS with or without ST-elevations with symptom onset during the previous 24 hours.

If there were no ST-elevations, patients were required to have at least 2 of 3 of the following: ST change reflecting ischemia, elevated cardiac biomarkers (i.e. troponin), or one of several risk factors (age ≥ 60, prior MI/CABG, CAD w/ ≥ 50% stenosis in ≥ 2 vessels, prior ischemic stroke/TIA/carotid stenosis ≥ 50%, DM, PAD, CrCl < 60)

Intervention: ticagrelor 180mg loading dose followed by 90mg BID + aspirin

Comparison: clopidogrel 300mg loading dose followed by 75mg daily + aspirin

Outcomes:
Primary: composite of death from vascular causes, MI, or CVA

Secondary

  • major bleeding (fatal bleeding, intracranial bleeding, intrapericardial bleeding w/ tamponade, hemorrhagic shock, decline of Hgb < 5.0, or requiring transfusion of 4 units pRBC)
  • all-cause mortality, MI, or stroke
  • composite of death from vascular mortality, MI, stroke, recurrent severe ischemia, recurrent ischemia, TIA, or other arterial thrombotic event
  • stent thrombosis

 

Results:
18,624 patients from 862 centers in 43 countries were recruited and enrolled in the study. 9,333 were randomized to the ticagrelor group, and 9291 were randomized to the clopidogrel group. Patients were followed for up to 12 months.

The two treatment groups did not statistically differ in baseline characteristics, non-study medications following randomization, or procedures following randomization. Both groups started the study drug at a median of 11.3 hours after the onset of chest pain.

The primary end point (death from vascular causes, MI, or CVA) occurred less often in the ticagrelor group than in the clopidogrel group – 9.8% vs 11.7% (HR 0.77 – 0.92; p < 0.001; NNT = 52.6).

The groups did not significantly differ in terms of major bleeding – 11.6% vs. 11.2% (HR 1.04; 95% CI 0.95 – 1.13; p = 0.43).

Patients who received ticagrelor trended toward an increased rate of intracranial bleeding (26 [0.3%] vs. 14 [0.2%], p = 0.06), including a statistically significant increase in fatal intracranial bleeding (11 [0.1%] vs. 1 [0.01%], p = 0.02) as well as non-CABG bleeding (4.5% vs. 3.8%, p = 0.03). However, there were fewer episodes of other types of fatal bleeding in the ticagrelor group.

Regarding other secondary outcomes, ticagrelor performed better in:

  • composite of all-cause, MI, or stroke – 10.2% vs. 12.3% (HR 0.84; 95% CI 0.77 – 0.92; p < 0.001; NNT 47.6)
  • composite of death from vascular causes, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic event – 14.6% vs. 16.7% (HR 0.88; 95% CI 0.81 – 0.95; p < 0.001; NNT 47.6)
  • stent thrombosis – 1.3% vs. 1.9% (HR 0.67; 95% CI 0.50-0.91; p = 0.009, NNT = 167).

Dyspnea was more common in the ticagrelor group than in the clopidogrel group (13.8% vs 7.8%, p < 0.001). There was a higher incidence of ventricular pauses in the first week in the ticagrelor group relative to the clopidogrel group; however, the two groups did not differ in incidence of syncope or pacemaker implantation. Discontinuation of study drug due to adverse event was more common in the ticagrelor group (7.4% vs. 6.0%). Ticagrelor was also associated with elevations in uric acid and creatinine.

Implication/Discussion:
PLATO demonstrated that treatment of ACS with ticagrelor (vs. clopidogrel) significantly reduced the rate of death from vascular causes, MI, or stroke, without increasing the risk of major bleeding.

 Although ticagrelor patients did demonstrate higher rates of intracranial and non-CABG bleeding, this bleeding did not qualify as “major bleeding.” They also complained more frequently of dyspnea (a known adverse effect of the drug). Discontinuation of ticagrelor due to dyspnea occurred in 0.9% of patients. Due to this risk of dyspnea, as well as the risk of elevated serum uric acid and creatinine, caution should be used in those with a history of COPD, asthma, CHF, gout, and CKD who are considering using ticagrelor.

Strengths of this study include that it was a double-blind, randomized controlled trial with a large patient population. Weaknesses include that the study was funded by AstraZeneca, manufacturers of Brilinta (the brand name of ticagrelor). Also, the study drug did not perform as well in North American sites or underweight patients, yet the authors do not offer clear explanations as to why.

Bottom line:
Patients with a high risk of thrombosis and a low risk of bleeding may benefit most from ticagrelor. Ticagrelor has a mortality benefit when compared to clopidogrel. But ticagrelor should be used with caution in those with pulmonary disease (e.g. COPD or asthma), CKD, and heart block (due to association with ventricular pauses).

Drug cost: At time of study. Ticagrelor: $108/month; Clopidogrel: $26/month


Further Reading/References
:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Long-term antiplatelet therapy after coronary artery stenting in stable patients”
4. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease

Summary by Patrick Miller, MD