cardiology year in review - boca raton regional …web.brrh.com/msl/im2018/day-1_friday/friday 5 -...

Cardiology year in review Joseph L. Blackshear, MD Professor of Medicine Mayo Clinic College of Medicine Mayo Clinic Florida

ORBITA trial

• Premise: no double blind studies of PCI in stable coronary artery disease

• Utilized sham PCI

• Inclusions: 18-85 yr, angina, ≥ 70% 1V stenosis

• Exclusions: ≥ 50% stenosis in 2nd vessel, ACS, prior CABG, left main CAD, contraindication to drug eluting stent, total occlusion, LV dysfunction, severe valvular disease, pulmonary hypertension

• Primary study endpoint: exercise time

©2012 MFMER | slide-3 Al-Lamee R Lancet 2108;391:31

ORBITA study phases and assessments

• 6 week period of optimization and up-titration of antianginal medications

• Pre-randomization assessments

• Randomization and procedure

• Post-randomization assessments


Seattle Angina Questionnairre

Cardiopulmonary Exercise Asssement of VO2 Max

Dobutamine Stress Echocardiography

Fractional Flow Reserve in cath lab durging PCI or Sham procedure

Quality of life measures

ORBITA outcomes

• 230 patients enrolled, 200 randomized, age 66

• 69% of lesions in left anterior descending

• Angina duration 9 months avg

• Baseline exercise time > 8 minutes avg

• Duke Treadmill score, 4+ =mild to mod risk

• Wall motion scores baseline=low risk

• Cath FFR negative for ischemia in 28-32%


ORBITA main findings

• With PCI, exercise time was 17 seconds higher than sham PCI (not significant)

• No differences in:

• Time to 1 mm ST depression

• Peak VO2 max

• Δ angina class

• Angina scores or QOL scores

• Duke treadmill score

• Dobutamine wall motion score improved with PCI


Authors and editorialists conclusions:

• Even with severe coronary stenosis patients treated with PCI do not receive symptomatic benefit compared to a sham procedure

• Wordwide up to ½ million PCI done for stable CAD

• In these, death 0.65%, MI 15%, AKI 13%, stroke 0.2%, vascular injury 2-6%

• PCI is routine, ingrained profitable

• PCI for stable CAD should be abandoned


Reactions

• Milton Packer quoted Upton Sinclair “It is difficult to get a man to understand something when his salary depends on not understanding it.”

• William Boden: This shows that placebo trials are possible and necessary

• Daniel Mark: Angina burden at baseline is a major determinant of effect size of an intervention-low angina burden in ORBITA reduced anticipated effectiveness of PCI and small small size reduced precision in measured effect size


High sensitivity cardiac troponin (CTn)

• Detect a low level of CTn in 20-50% of normals

• Detect a low level of CTn in 90% of diabetics

• Precise at low concentrations, in contrast to current generation assays

• In use in Europe and elsewhere for a few years

• Coming soon to your laboratory

• How to rule MI out and in?



Twerenbold R, JACC 2017;70:996

High sensitivity troponin T one hour algorithm (2 or 3 hr below)

2 and 3 hr algorithm: MI ruled out if 0 hour <14 ng/l and 2 or 3 hr Δ < 4 ng/l

MI ruled in if 0 hour ≥ 53 ng/l or 2 hour Δ ≥ 10 ng/l

Sodium glucose co-transporter 2 inhibitors in type II diabetes

• Empaglifozin reduced CV events and death

• Liraglutide reduced CV death, non-fatal MI and stroke

• Semaglutide reduced CV death, non-fatal MI and stroke


NEJM 2015

NEJM 2016

NEJM 2016

Cangaflozin (class effects of SGLT2 inhibitors)

• Lower plasma glucose by facilitating glycosuria

• Natriuresis

• Mild osmotic diuresis

• Net caloric loss – weight and systolic BP ↓


↑Na delivery to renal macula densa normalizes

intraglomerular pressure, improves renal function

Post hoc study of cangaflozin vs placebo

• 666 pts tested at baseline, then 26, 52,104 wks

• Type II DM, age 55-80, Hb A1C 7-10, GFR≥50

• Excluded if history of MI, unstable angina, prior coronary revascularization, stroke within 3 months, NYHA class III/IV symptoms, or uncontrolled hypertension

• High sensitivity troponin I and NT pro-BNP



Januzzi JL JACC 2017;70:704

Conclusions

• Cangaflozin attenuated the rise in cardiac biomarkers of known prognostic importance in type II diabetes


Evolocumab, a PSCK9 inhibitor (↓ LDLc by 60%)

• 27,564 patients with ASCVD and LDLc ≥ 70 mg/dl and on statin

• SQ 140 mg Q 2 wk or 420 mg monthly or Placebo

• Primary outcome: CV death, MI stroke, unstable angina hospitalization, or coronary revascularization

• Median follow-up 2.2 years; no ↑ DM or ↓ cognition

• LDLc reduced from 92 to 30 mg/dl

• Primary outcome reduced from 11.3% to 9.8%, a 15% relative risk reduction (p<0.001)

• ASCVD pts benefit from ↓ LDLc beyond current treatment targets


Sabatine MS NEJM 2017;376:1713

Clonal hematopoiesis of indeterminate potential (CHIP) and atherosclerosis

• Spontaneous somatic mutations in bone marrow leukocyte progenitor cells

• These cells retain (and are advantaged) to differentiate into PMNs, lymphs, monocytes

• Rare before age 40, but about 10% at age 70

• 10 X ↑ risk of hematologic cancers

• Two fold increased risk of CAD

• Four fold increased risk of MI in the young

• Leukocyte cytokines implicated by mouse studies


Jaiswal S NEJM 2017;377:111

Canakinumab, antibody to interleukin-1ᵝ

• Anti-inflammatory agent approved in rheumatologic pts

• 3 doses vs placebo in post-MI patients + hsCRP> 2

• Exclusions: chronic / recurrent infection, prior cancer, immunocompromised state, history of TB, risk of TB, HIV associated disease, or use of systemic anti-inflammatories

• SQ injection every 3 months

• Outcome variables: CV death, nonfatal MI or stroke

• Key secondary outcome included unstable angina hospitalization for urgent revascularization

• Follow up 3.7 years


©2012 MFMER | slide-24 Ridker PM, NEJM 2017;377:1119

Events/

100 pt yr

4.5

4.11

3.86

3.9

No effects on lipids seen

15% relative risk reduction for primary endpoint at the 150 mg dose


Ridker PM, NEJM 2017;377:1119

Targeting inflammation led to reduced secondary endpoints

indpendent of lipid lowering


Heart failure

CASTLE-AF trial

• Patients with paroxysmal or permanent AF

• Randomized to ablation (n=179) vs rate or rhythm control (n=184), 3 yr follow-up

• Intolerant / unwilling to take / ineffective drugs

• EF ≤ 35%, and class II-IV heart failure

• ICD in place

• Primary outcome: death or HF hospitalization


Marrouche NF, NEJM 2018;378:417


Marrouche NF, NEJM 2018;378:417

AF at follow-up

Ablation 63%

Control 22%

Change in EF:

Ablation + 8%

Conrtol + 0.2%

New BP management guidelines

How did this happen?

Systolic hypertension in the elderly, SHEP; age ≥ 60, SBP ≥ 160

Chlorthalidone 1st, then add atenolol

1998: new diabetes in 8.6% vs 7.5%

JAMA, 1991

Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial.

Systolic BP, SPRINT Systolic BP, SHEP

SHEP, 1991

SHEP 1997

Overall 49% RRR in heart failure

Age 60-69

Age 70-79

Age 80-89

Primary Outcome and Death from Any Cause.

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

SPRINT, NEJM 2015

Primary outcome composite MI or ACS, stroke, new heart failure, or CV death

Standard BP group – SPRINT protocol

• …standard Group participants on previous antihypertensive drug therapy should be converted to SPRINT medications or no medications, depending on what…is most likely to achieve a SBP level between 135-139 mm Hg.

• Because we expect a decrease in SBP within the Standard Group following randomization………….. treatment should not be intensified at the randomization visit unless SBP ≥160 mm Hg……Down titration should be carried out if the SBP is <130 mm Hg at a single visit or <135 mm Hg at two consecutive visits

RESEARCH ARTICLE

Benefit and harm of intensive blood pressure

treatment: Derivation and validation of risk

models using data from the SPRINT and

ACCORD trials

Sanjay Basu1,2,3,4*, Jeremy B. Sussman5,6,

Joseph Rigdon7, Lauren Steimle8, Brian

T. Denton8, Rodney A. Hayward5,6

Personalizing the Intensity of Blood Pressure

Control

Modeling the Heterogeneity of Risks and

Benefits From SPRINT

(Systolic Blood Pressure Intervention Trial)

Krishna K. Patel, MD; Suzanne V. Arnold, MD,

MHA; Paul S. Chan, MD, MSc;

Yuanyuan Tang, PhD, Yashashwi Pokharel,

MD, MSCR; Philip G. Jones, MS;

John A. Spertus, MD MPH

BP Goal for Patients With Hypertension

COR LOE Recommendations for BP Goal for Patients

With Hypertension

I

SBP:

B-RSR

For adults with confirmed hypertension and known

CVD or 10-year ASCVD event risk of 10% or higher

a BP target of less than 130/80 mm Hg is

recommended. DBP:

C-EO

IIb

SBP:

B-NR

For adults with confirmed hypertension, without

additional markers of increased CVD risk, a BP

target of less than 130/80 mm Hg may be

reasonable.

DBP:

C-EO

SR indicates systematic review.

Blood Pressure (BP) Thresholds and Recommendations for Treatment and Follow-Up (continued on next slide)

Normal BP(BP <120/80

mm Hg)

Promote optimal lifestyle habits

Elevated BP(BP 120–129/<80

mm Hg)

Stage 1 hypertension(BP 130–139/80-89

mm Hg)

Nonpharmacologic therapy(Class I)

Reassess in 3–6 mo(Class I)

BP goal met

No Yes


Assess and optimize

adherence to therapy

Consider intensification of

therapy

Reassess in 1 mo

(Class I)

Nonpharmacologic therapy and

BP-lowering medication(Class I)

Reassess in 1 y

(Class IIa)

Clinical ASCVD or estimated 10-y CVD risk

≥10%*

YesNo

Nonpharmacologic therapy (Class I)

BP thresholds and recommendations for treatment and follow-up

Nonpharmacologic therapy and

BP-lowering medication†(Class I)


Stage 2 hypertension(BP ≥ 140/90 mm Hg)

Choice of Initial Medication, on line risk calculator

COR LOE Recommendation for Choice of Initial Medication

I

ASR

For initiation of antihypertensive drug therapy, first-

line agents include thiazide diuretics, CCBs, and

ACE inhibitors or ARBs.

SR indicates systematic review.

https://sanjaybasu.shinyapps.io/intbp/

Basu S, Sussman J, Rigdon J, Steimle L, Denton B, Hayward R. Risk calculator

for benefit and harm

from intensive blood pressure treatment. Palo Alto: Stanford University; 2017

[cited 2017 Sep 26].

Available: http://sanjaybasu.shinyapps.io/intbp.

Yields number needed to treat: 1 = ideal. The lower the better, < 40 good.

It is the inverse of absolute risk reduction and gives number of pts who need to

be treated to prevent one outcome event

https://sanjaybasu.shinyapps.io/intbp/

http://sanjaybasu.shinyapps.io/intbp

2017 in review

• ORBITA trial suggested no benefit from PCI in stable significant one vessel CAD

• High sensitivity troponin abnormal in most; we all need to learn new rule-in and -out levels

• SGLT2 inhibitors reduce clinical and subclinical cardiovascular events (Tn and BNP)

• PCSK9 inhibitor reduced CV events and LDLc

• Clonal hematopoiesis ↑ CAD; Canakinumab (IL 1 beta inhibitor) reduced CRP and CV events

• Heart failure: replace ACE with ARNI, ablate Afib

• Blood pressure: Target < 130 for those at risk, use thiazides, ACE/ARB, calcium blockers


cardiology year in review - boca raton regional …web.brrh.com/msl/im2018/day-1_friday/friday 5 -...

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