heart outcomes prevention evaluation (hope) -...

HEART OUTCOMES PREVENTION EVALUATION (HOPE) - 3:

Study of Lipid Modification and Blood Pressure Reduction in People at Average Risk

Alexandra Goncharenko, PharmD, BCPSPGY2 Cardiology Pharmacy Resident

University of Illinois at Chicago College of PharmacyPresenter

Karen J McConnell, PharmD, FCCP, BCPS-AQ Cardiology, ASH-CHCClinical Director, Cardinal Health

Clinical Associate Professor, University of Colorado Skaggs School of PharmacyMentor

May 31, 2016

Disclosure

I have no conflict of interest to disclose.

Background

• Myocardial infarction (MI), stoke and other atherosclerotic cardiovascular diseases (CVD) are major causes of death and serious morbidity

• Epidemiologic studies have established the major modifiable risk factors that account for > 90% of the population attributable risk for MI

– Of the known risk factors, abnormal lipids and elevated blood pressure account for > 66% of the risk for MI

Roth GA, et al. N Engl J Med 2015;372:1333-41. Lewington S, et al. Lancet 2002;360:1903-13.

Yusuf S, et al. Lancet 2004;364:937-52.O’Donnell MJ, et al. Lancet 2010;376:112-23.

Background

• Age is the most discriminatory risk factor in identifying individuals at highest risk for CVD– > 90% of deaths from ischemic heart disease or stroke

occur in people > 55 years old

• Current efficacy studies target treatment in subjects with high CV risk factors – High-risk individuals represent < 20% of those in

middle age and among whom < 33% of all CVD events occur

– Results in a lack of treatment for patients with “average” levels of risk

Law MR, et al. BMJ 2002;324:1570-6. Yusuf S, et al. N Engl J Med. 2016. [Epub ahead of print]

Recent Trials

SPRINT – NEJM 2015

• Randomized 9,300 persons aged > 50 years with at least one CV risk factor or renal disease (without DM or stroke) to SBP < 120 mmHg or < 140 mmHg

• 25% were > 75 years old, 3.26 year follow-up

• Primary composite outcome in the < 120 mmHg arm significantly lower than the < 140 mmHg arm

JUPITER – NEJM 2008

• Randomized 17,802 participants; men > 50 years, women > 60 years with no history of CVD, LDL < 130 mg/dL, and hxCRP > 2 mg/L to rosuvastatin 20 mg/day or placebo

• 1.9 year follow-up

• Primary outcome of first major CV event in the rosuvastatin arm was significantly lower than placebo

Wright JT, et al. N Engl J Med. 2015;373(22):2103-16.Ridker PM, et al. N Engl J Med. 2008;359(21):2195-207.

Study Objectives

• In individuals at average CVD risk and without known CVD:

1. Evaluate the effects of lipid modification with rosuvastatin 10 mg daily on major CV events

2. Evaluate the effects of blood pressure lowering with candesartan 16 mg/HCTZ 12.5 mg daily on major CV events

3. Evaluate the impact the the two combined interventions

Yusuf S, et al. N Engl J Med. 2016. [Epub ahead of print]

Study Design: Trial Design

• Large, multi-center, international randomized placebo-controlled trial

• 2 x 2 factorial design

• Intervention:CANDESARTAN/HCTZ

ACTIVE PLACEBO

RO

SUV

AST

ATI

N

AC

TIV

E

Rosuvastatin 10 mg +Candesartan/HCTZ 16/12.5 mg

Rosuvastatin 10 mg + Placebo

PLA

CEB

O

Placebo + Candesartan/HCTZ 16/12.5 mg

Placebo + Placebo


Inclusion and Exclusion Criteria

INCLUSION EXCLUSION

• Women aged > 65 years and men > 55 years

• One additional CV risk factor:•Waist-to-hip ratio > 0.85 in women, > 0.9

in men•History of current or recent smoking

(within 5 years)• Low HDL cholesterol (< 40 mg/dL in men

and < 50 mg/dL in women•Dysglycemia (IFG, IGT) or uncomplicated

diabetes controlled by diet or < 1 drug•Renal dysfunction (GFR < 60 mL/min, SCr

> 1.4 mg/dL, microalbuminuria)• Family history of early CHD in first

degree relatives (age < 55 years in men, < 65 years in women)

• Documented CVD• Clear indication or contraindication for

statin and/or ACE inhibitor/ARB and/or thiazide diuretic

• Symptomatic hypotension• Chronic liver disease• Inflammatory muscle disease• Severe renal impairment• Concurrent treatment with

• cyclosporine or a condition likely to result in transplant and need for cyclosporine

• Statin or fibrate• ARB, ACE inhibitor, thiazide diuretic

• Other serious medical illness


Study Procedures and Visit Schedule

• Screening: community-based, family practices

• Run-in: receive both drugs for 4 weeks, only selected subjects who can tolerate study intervention and procedures, likely to have high adherence

• Follow-up: patients seen at 6 weeks and then every 6 months for data collection, assessment of side effects and adherence, and laboratory measurements


Study Procedures and Visit Schedule

• Concurrent Treatments: no restrictions to the use of additional therapies (encouraged use of drugs other than statins, ARBs, ACE inhibitors, and thiazide diuretics)

• Adherence + lifestyle advice: evaluated and reinforced at every study visit

• Extended Follow-up: May 2013 – May 2018; annual assessment of major CV events


Study Outcomes

Co-Primary Outcomes

• The composite of CV death, non-fatal MI, non-fatal stroke

• The composite of CV death, non-fatal MI, non-fatal stroke and [resuscitated cardiac arrest, heart failure, and revascularization]

Secondary Outcome

• Components of the second co-primary outcome and angina with evidence of ischemia

• (BP study only) Fatal and nonfatal strokes

Tertiary Outcomes

• Components of the co-primary outcomes

• All-cause mortality

• New-onset diabetes mellitus

• Cognitive function (in participants > 70 years of age)

• Not reported in original article

• Erectile dysfunction

• Not reported in original article


Predefined Subgroup Analysis

• Gender

• Age

• Pre-treatment LDL cholesterol

• HDL cholesterol

• Apo B/Apo A-1 ratio

• Pre-treatment blood pressure

• Waist-to-Hip Ratio

• Ethnicity


Statistical Analysis

• Intention-to-treat analysis • Expected event rates:

– First co-primary outcome in dual-placebo group rate = 1%– Cumulative nonadherence rates = 23%– Drop-in rates = 11%– Loss to follow-up rate = < 1%

• Needed to enroll 12,700 patients to achieve 80% power to detect a risk of the co-primary outcomes with dual therapy at least 35% lower than the risk with dual placebo

• Survival curves for were plotted using Kaplan-Meier and log-rank test

• Cox proportional-hazards model was used to estimate treatment effects and effects in subgroups

• Type I error rate = 5% with a P value < 0.05


Trial Participants

14,682 screened for eligibility

1,977 (13.5%) excluded

12,705 randomized (86.5%)

3,180 assigned Candesartan/HCTZ

Rosuvastatin

3,181 assigned Placebo

Rosuvastatin

3,176 assigned Candesartan/HCTZ

Placebo

3,168 assigned PlaceboPlacebo


Baseline Characteristics

CharacteristicCandesartan/HCTZ +

RosuvastatinRosuvastatin +

PlaceboCandesartan/HCTZ +

PlaceboPlacebo + Placebo

Age (yr) 65.7±6.3 65.8±6.4 65.6±6.4 65.7±6.3

Female (%) 46.1 46.7 45.5 46.7

Race (%)

Chinese or Asian 48.9 49.2 49.1 49.1

Hispanic 27.2 27.7 27.6 27.7

White 20.5 20.0 19.9 19.8

Black 1.8 1.7 1.8 1.7

CV risk factor (%)

WHR 87.1 87 86.3 86.9

HTN 37.7 37.8 37.7 38.3

Low HDL 37.8 35.9 34.5 36.2

Smoking 28.0 26.8 28.1 28.1

FH of CHD 26.2 26.4 26.3 26.1

Baseline Characteristics cont.

CharacteristicCandesartan/HCTZ +

RosuvastatinRosuvastatin +

PlaceboCandesartan/HCTZ +

PlaceboPlacebo + Placebo

Blood Pressure (mmHg)

SBP 138.2±14.8 137.9±15.0 138.2±14.7 137.9±14.6

DBP 81.9±9.4 81.8±9.3 82.0±9.3 81.8±9.2

Heart Rate (bpm) 73.0±10.3 72.6±10.2 72.9±10.1 72.5±10.3

BMI (kg/m2) 27.2±4.8 27.1±4.8 27.1±4.8 27.1±4.7

WHR 0.94±0.08 0.94±0.08 0.94±0.08 0.94±0.09

Cholesterol

Total 201.3±43.5 201.8±41.6 201.5±41.7 201.2±41.7

LDL 127.0±37.0 128.6±35.2 127.9±36.0 127.9±36.0

HDL 44.7±14.1 44.8±13.7 45.1±13.7 44.8±13.8

Serum Creatinine(mg/dL)

0.90±0.22 0.89±0.22 0.90±0.22 0.90±0.21

Baseline Characteristics cont.

CharacteristicCandesartan/HCTZ

+Rosuvastatin

Rosuvastatin + Placebo

Candesartan/HCTZ +

Placebo

Placebo + Placebo

Medication use (%)

Calcium-channelblocker

14.0 15.6 15.2 14.5

Aspirin 11.3 10.3 12.0 10.3

Beta-blocker 8.1 7.7 8.3 7.9

5% or less: • Oral hypoglycemic• Alpha-blocker• Niacin• Ezetimibe• Aldosterone antagonist• Non-thiazide diuretic

RESULTS: BLOOD PRESSURE ARMHOPE-3 Trial

Lonn EM, et al. N Engl J Med. 2016. [Epub ahead of print]

Systolic Blood Pressure Lowering

138 mmHg

134 mmHg

128 mmHg

Δ 6 mmHg

PLACEBO

Candesartan/HCTZ


Diastolic Blood Pressure Lowering

82 mmHg

79 mmHg

76 mmHgΔ 3 mmHg

PLACEBO

Candesartan/HCTZ


Blood Pressure Arm: Results

Outcome Candesartan/HCTZ(N=6,356)

Placebo(N=6,349

)HR 95% CI

First coprimary 260 (4.1) 279 (4.4) 0.93 0.79-1.10

Second coprimary 312 (4.9) 328 (5.2) 0.95 0.81-1.11

Secondary

First Secondary 335 (5.3) 364 (5.7) 0.92 0.79-1.06

Fatal or nonfatal Stroke 75 (1.2) 94 (1.5) 0.80 0.59-1.08

• No difference in:• Components of the co-primary and secondary outcomes• All-cause mortality• New-onset diabetes mellitus


Blood Pressure Arm: Subgroup Analysis Results

RESULTS: LIPID ARMHOPE-3 Trial


LDL Cholesterol Lowering

• Baseline = 127.8 mg/dL

• End of the trial = i29.5 mg/dL

• Overall mean difference = i34.6 mg/dL

• ~25% reduction in LDL

Lipid Lowering Arm: Results

Outcome Rosuvastatin(N=6,361)

Placebo(N=6,344

)HR 95% CI NNT

First coprimary 235 (3.7) 304 (4.8) 0.76 0.64–0.91 90

Second coprimary 277 (4.4) 363 (5.7) 0.75 0.64–0.88 76

Secondary 306 (4.8) 393 (6.2) 0.77 0.66–0.89 71

Coronary Heart Disease

105 (1.7) 140 (2.2) 0.74 0.58–0.96 200

CV hospitalizations 281 (4.4) 369 (5.8) 0.75 0.64–0.88 71

• No difference in: • All-cause mortality• New-onset diabetes mellitus• Any subgroup analyses

RESULTS: COMBINATION THERAPYHOPE-3 Trial

Combination Therapy: Results

Outcome Cand/HCTZ+Rosuva

(N=3,180)

Placebo+Placebo

(N=3,168)HR 95% CI NNT

First coprimary 113 (3.6) 157 (5.0) 0.71 0.56–0.90 71

Second coprimary 136 (4.3) 187 (5.9) 0.72 0.57–0.89 62

Secondary 147 (4.6) 205 (6.5) 0.71 0.57–0.87 52

CV hospitalizations 141 (4.4) 191 (6.0) 0.73 0.59–0.91 62

• No difference in:• All-cause mortality• New-onset diabetes mellitus• Any subgroup analyses

Safety

• Candesartan/HCTZ vs placebo:– Increased symptomatic hypotension, dizziness, or light-

headedness (3.4% vs 2.0%, P<0.0001)– No difference in syncope– No difference in renal dysfunction or potassium abnormalities

• Rosuvastatin vs placebo:– Increased muscle pain or weakness (5.8% vs 4.7%, P=0.005)– No difference in discontinuation rates due to above events– No difference in number of cases of rhabdomyolysis or

myopathy– No difference in rates of cancer

• Similar results for combination therapy

Conclusions

• Compared to placebo, treatment for a median 5.6 years, in intermediate-risk persons with…– Candesartan/HCTZ 16/12.5mg daily:

• Lowered SBP by 6 mmHg from baseline

• Did not decrease risk of major CV events

• Significant benefit seen in subgroup with baseline SBP > 143 mmHg

– Rosuvastatin 10mg daily:• Lowered LDL by 39.6 mg/dL from baseline

• Decreased risk of major CV events

– Combination therapy:• Lowered SBP by 6 mmHg from baseline

• Lowered LDL by 33.7 mg/dL from baseline

• Decreased risk of major CV events

Conclusions cont.

• Blood Pressure Arm– HOPE-3 versus SPRINT:

• HOPE-3 had a lower risk population with low rates of hypertension at baseline, gave antihypertensive drug therapy and found no CV benefit

• SPRINT used a higher risk population with hypertension at baseline, used a treat-to-target approach and found a CV benefit

– Results of HOPE-3:• Confirm starting antihypertensive treatment in persons

without CVD with SBP ~140 mmHg• Suggest a lack of benefit initiating antihypertensive

treatment in persons who are not hypertensive (SBP < 140 mmHg)

Conclusions cont.

• Lipid Arm– HOPE-3 versus JUPITER:

• HOPE-3 had a smaller difference in reduction of CV events and smaller LDL cholesterol lowering than JUPITER, but risk was still reduced regardless of entry LDL

• Confidence intervals between the 2 trials overlap • HOPE-3 saw similar benefits regardless of baseline CRP

– Short mean duration of treatment may actually underestimate the real benefits of long-term treatment

– Suggest benefit of using a simple approach to treatment• Minimizes use of laboratory testing

Conclusions cont.

• Combination Therapy Arm– Rates of adherence were high, so degree of LDL and BP lowering likely

representative to real-world – If greater LDL and SBP reductions with a more intense drug regimen

were achieved, greater benefit in CV outcomes?– Combination therapy was associated with a significantly lower rate

of cardiovascular events than dual placebo among persons at intermediate risk who did not have CVD

– Simple approach to patient selection: age + easily measured risk factors

- All 3 arms:- Trial included persons of diverse racial and ethnic groups from 21

countries with board consistency in benefits and safety- Confirmation of safety:

- No significant differences between new-onset DM, renal dysfunction, syncope, liver-function abnormalities, eye problems, or cancers

- Despite higher muscle pain and dizziness in the combination therapy group, effects were generally reversible with temporary discontinuation

Critique

• None of the patients enrolled were from the US

• Real-world adherence rates are actually lower

• LDL reduction was lower than expected– Moderate-intensity statin expect at least 30-50%

LDL reduction

• Additional BP reduction (and possibly benefit) may have been seen if higher dose of candesartan or a different thiazide had been used

• Added benefits present at > than 5 years?

Impact on Clinical Practice

• 2013 ACC/AHA Cholesterol Guidelines

– Assess ASCVD risk and treat > 7.5% with statins

– No apparent need for routine LDL monitoring

• 2013 JNC 8 panel recommendations

– Clear evidence to initiate treatment in patients with SBP > 143 mmHg

– Lack of evidence for increased BP goal of 150/90 mmHg in patients aged > 60 years

Acknowledgements

• Journal Club Mentor:

– Karen J McConnell, Pharm.D., FCCP, BCPS-AQ Cardiology, ASH-CHC

• Program Director:

– Rob DiDomenico, Pharm.D., FCCP, BCPS-AQ Cardiology

• ACCP Cardiology PRN Journal Club Coordinators:

– Carrie S. Oliphant, Pharm.D., FCCP, BCPS-AQ Cardiology

– Ted Berei, Pharm.D., MBA

– Zachary Noel, Pharm.D., BCPS

heart outcomes prevention evaluation (hope) -...

Documents