HOPE-3 Cholesterol

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Yusuf S, et al. "Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease". The New England Journal of Medicine. 2016. :.
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Note
This is a merged review of HOPE-3 BP, HOPE-3 Cholesterol, and HOPE-3 BP & Cholesterol that will be trimmed down to reflect the specific review

Clinical Question

Among patients with intermediate cardiovascular disease risk, does rosuvastatin, hydrochlorthiazide/candesartan, or a combination of both interventions reduce cardiovascular events?

Bottom Line

Rosuvastatin reduces cardiovascular events in patients with intermediate cardiovascular risk. Combination with hydrochlorothiazide/candesartan may help further reduce events in patients with a higher systolic blood pressure.

Major Points

The benefit of lipid and blood pressure lowering agents in patients with high cardiovascular risk is well-established in the literature. However, high-quality evidence in regards to similar treatment of those with intermediate cardiovascular risk is lacking. In addition, most studies to date investigating the benefits of cardiovascular risk reduction have predominantly included only white populations.

Published in April 2016, the HOPE-3 (Heart Outcomes Prevention Evaluation) trial is a 2x2 factorial design, multinational, double-blinded, placebo-controlled trial performed in an ethnically diverse population. It was conducted in patients with intermediate cardiovascular risk, defined as a 1% annual risk of a cardiovascular event, to determine whether lipid-lowering agents, blood pressure-lowering agents, or a combination of agents would reduce major cardiovascular events. A total of 12,705 patients were randomized to rosuvastatin, hydrochlorothiazide and candasartan, all three medications, or placebo only. This study was published in a set of 3 different journal articles, analyzing the differences between patients receiving lipid-lowering agents vs. placebo, blood pressure-lowering agents vs. placebo, or combined blood pressure and lipid-lowering agents vs placebo. There were two co-primary endpoints in this trial, identical in all three articles. The first endpoint was a composite of cardiovascular death, myocardial infarction and stroke. The second endpoint combined the first endpoint with resuscitated cardiac arrest, heart failure, and revascularization. Median followup was 5.6 years.

Of note, drug doses were fixed and not titrated to specific targets throughout the trial. In addition, there were no lipid profile or blood pressure cutoffs that were present in the exclusion criteria. Patients with a clearly known indication for the prescribed medications were excluded from this study (e.g. known CAD, significant DM, significant renal disease) as they would not be of intermediate risk.

In the lipid-lowering study, both the first co-primary (3.7% vs. 4.8%; HR 0.76; 95% CI 0.64-0.91; NNT=90) and second co-primary (4.4% vs. 5.7%; HR 0.75; 95% CI 0.64-0.88; NNT=77) outcomes were statistically significant, in favor of rosuvastatin. Similar findings were present in both the first (3.6% vs. 4.6%; HR 0.71; 95% CI 0.56-0.90; NNT=100) and second co-primary outcomes in the combined therapy study) (4.3% vs. 5.9%; HR 0.72; 95% CI 0.57-0.89; NNT=63). In contrast, neither co-primary outcomes were significant in the BP-lowering study. Total strokes were not decreased with BP-lowering agents.

The beneficial effect of lipid-lowering agents is consistent with previous trials investigating primary prevention with statins in intermediate risk populations, including the JUPITER and MEGA trials. However, whether treatment with a combination of both BP-lowering and lipid-lowering agents is superior to lipid-lowering agents alone is unclear. A post-hoc analysis performed suggested there was a reduction in the primary endpoints when combination therapy was given to patients with a higher baseline systolic BP (upper tertile) compared to lower (lower two tertiles), although the interaction analysis was not statistically significant. Similarly, the sub-group analysis in the BP-lowering study showed patients with higher baseline systolic blood pressures trended towards significant reductions in the primary endpoints, but the applicability of this analysis is also unclear.

In summary, HOPE-3 provides strong evidence favoring the use of statin therapy in the primary prevention of cardiovascular disease in those with intermediate risk across an ethnically diverse population even without regular drug titration to prespecified targets. Antihypertensives may further reduce cardiovascular disease in those with higher baseline systolic blood pressures. The results of HOPE-3 helps further pave the way to the development of a "polypill", a combination of multiple medications for the primary prevention of cardiovascular disease in a large segment of the general population at lower baseline risk.

Guidelines

No guidelines as of April 2016 reflect the outcomes of this trial.

Design

  • Multicenter, international, double-blind 2x2 factorial design placebo-controlled trial
  • N=12,705 patients with intermediate cardiovascular disease risk
    • Statin Study: Rosuvastatin (n=6,361) vs. Placebo (n=6,344)
    • BP Study: Candesartan/HCTZ (n=6,356) vs. Placebo (n=6,349)
    • Statin/BP Study: Rosuvastatin + Candesartan/HCTZ (n=3,180) vs. Rosuvastatin + Placebo (n=,3181) vs. Candesartan/HCTZ + Placebo (n=3,176) vs. Placebo + Placebo (n= 3,181)
  • Follow-up: Median 5.6 years
  • Analysis: Intention-to-treat
  • Co-primary outcomes (all studies)
    • Composite of cardiovascular death, MI, stroke
    • Above outcome, plus resusciated cardiac arrest, heart failure, revascularization
  • Secondary outcome (all studies)
    • All primary outcomes, plus angina with evidence of ischemia
  • Secondary outcomes (BP study only)
    • Fatal and nonfatal strokes

Population

Inclusion Criteria

  • Women ≥65 years and men ≥55 years
  • 1 or more CV risk factors
    • Waist/hip ratio ≥0.85 (women) or ≥0.90 (men)
    • Smoker or recent ex-smoker (last 5 years)
    • HDL-C < 1.3mmol/L (women) or < 1.0mmol/L (men)
    • Dysglycemia (IFG, IGT, uncomplicated diet controlled DM)
    • Early renal dysfunction (eGFR<60, Cr>1.4mg/dL, microalbuminuria)
      • excluded if hypertensive (BP > 130/80) or proteinuria present
    • Family history of early CHD (M<55y, F<65y)

Exclusion Criteria

  • Documented, clinically manifest atherothrombotic CVD
  • Any statin, ARB, ACE inhibitor, or thiazide indication
  • Statin, ARB, or thiazide contraindication
  • Chronic liver disease or high LFTs (3x ULN)
  • Inflammatory muscle disease or high CK (3x ULN)
  • Moderate renal dysfunction (eGFR<45 or Cr>2mg/dL)
  • Fibrate or cyclosporine treatment
  • Symptomatic hypotension
  • Serious condition interfering with trial completion or participation
  • Use of experimental pharmacological agent

Baseline Characteristics

Demographics

From the rosuvastatin arm of the statin study. Note: This was chosen because of 1) larger N size than the combined study; 2) statin paper results of most interest. Really all the data is similar anyway.

  • Age (mean): 66 years
  • Female: 46%
  • Race: 29% Chinese, 27% Hispanic, 20% White, 15% South Asian, 5% Other Asian, 2% Black, 2% Other
  • BP: 138/82 mmHg
  • HR: 82BPM
  • BMI: 27
  • Waist-to-hip ratio: 0.94
  • Interheart Risk Score: 14.5

Cardiovascular Risk Factors

  • Risk Factors:
    • Elevated waist-to-hip ratio: 87%
    • Smoking: 27%
    • Low HDL: 37%
    • IGT/IFG: 13%
    • Early DM: 6%
    • Premature CHD Family History: 26%
    • Early renal dysfunction: 3%
    • Hypertension: 38%
  • 2+ Risk Factors: 47%
  • 3+ Risk Factors: 24%

Biochemical

  • Lipid Profile
    • Total cholesterol: 202 mg/dL
    • LDL: 128 mg/dL
    • HDL: 45 mg/dL
    • Triglycerides: 129 mg/dL
  • Fasting glucose: 95 mg/dL
  • HsCRP: 2mg/L
  • Serum Cr: 0.89 mg/dL

Baseline Medications

  • Calcium channel blocker: 15%
  • ASA: 11%
  • Beta-blocker: 8%
  • Oral hypoglycemic agent: 3%
  • 1% or less: alpha-blocker, niacin, ezetimibe, aldosterone antagonist, nonthiazide diuretic

Interventions

  • Eligible patients underwent a single-blind run-in phase receiving both cholesterol & BP-lowering agents for 4 weeks, and were excluded for poor adherence or unacceptable adverse events
  • Randomization in 2 by 2 factorial design:
    • Randomization A: Lipid-lowering Arm vs. Placebo
    • Randomization B: BP-Lowering Arm vs. Placebo
  • Arm-Specific Interventions
    • Lipid-lowering Arm: rosuvastatin 10mg daily
    • BP-lowering arm: candesartan 16mg daily and hydrochlorothiazide 12.5mg daily
  • General Interventions
    • Individualized structured lifestyle advice
  • Follow-up
    • Visits at 6 weeks, 6 months, then every 6 months thereafter
    • Blood pressure measured at every visit in the first year, then annually
    • Lipid levels at 1 year, 3 years and end of trial in an ethnically representative subsample of 10-20% of participants
  • Open-label statins could be prescribed, but the assigned statin-arm regimen (rosuvastatin or placebo) would be discontinued

Outcomes

Comparisons are intervention vs. placebo.

Primary Outcomes

P values of significance were adjusted to p=0.04 and p=0.02 for the below outcomes respectively, to preserve an overall type I error rate of 5% in testing two outcomes in each study."

Cardiovascular death, MI, or stroke
Statin study: 3.7% vs. 4.8% (HR 0.76; 95% CI 0.64-0.91; P=0.002)
BP-lowering study: 4.1% vs. 4.4% (HR 0.93; 95% CI 0.79-1.10; P=0.40)
Statin/BP-lowering study: 3.6% vs. 4.6% (HR 0.71; 95% CI 0.56-0.90; P=0.001)
Above outcome, plus resuscitated cardiac arrest, heart failure, revascularization
Statin study: 4.4% vs. 5.7% (HR 0.75; 95% CI 0.64-0.88; P<0.001)
BP-lowering study: 4.9% vs. 5.2% (HR 0.95; 95% CI 0.81-1.11; P=0.51)
Statin/BP-lowering study: 4.3% vs. 5.9% (HR 0.72; 95% CI 0.57-0.89; P=0.001)

Secondary Outcomes

All primary outcomes, plus angina with evidence of ischemia
Statin study: 4.8% vs. 6.2% (HR 0.77; 95% CI 0.66-0.89; P<0.001)
BP-lowering study: 5.3% vs. 5.7% (HR 0.92; 95% CI 0.79-1.06; p=0.26)
Statin/BP-lowering study: 4.6% vs. 6.5% (HR 0.71; 95% CI 0.57-0.87; P=0.001)
Fatal or nonfatal stroke
BP-lowering study: 1.2% vs. 1.5% (HR 0.80; 95% CI 0.59-1.08; P=0.14)

Primary/Secondary Outcomes, Components

Cardiovascular death
Statin study: 2.4% vs. 2.7% (HR 0.89; 95% CI 0.72-1.11)
Bp-lowering study: 2.4% vs. 2.7% (HR 0.91; 95% CI 0.73-1.13)
Statin/BP study: 2.4% vs. 2.9% (HR 0.82, 95% CI 0.60-1.11)
All MIs
Statin study: 0.7% vs. 1.1% (HR 0.65; 95% CI 0.44-0.94)
Bp-lowering study: 0.8% vs. 1.0% (HR 0.84; 95% CI 0.58-1.21)
Statin/BP study: 0.7% vs. 1.2% (HR 0.55; 95% CI 0.32-0.93)
All strokes
Statin study: 1.1% vs. 1.6% (HR 0.70; 95% CI 0.52-0.95)
BP-lowering study: 1.2% vs. 1.5% (HR 0.80; 95% CI 0.59-1.08) *This was a secondary endpoint, here for comparison purposes*
Statin/BP study: 1.0% vs. 1.7% (HR 0.56; 95% CI 0.36-0.87)
Resuscitated Cardiac Arrest
Statin study: 0.1% vs. 0.1%
Bp-lowering study: <0.1% vs. 0.1% (HR 0.33, 95% CI 0.07-1.65)
Statin/BP study: <0.1% vs. 0.1% (HR 0.33, 95% CI 0.03-3.18)
Revascularization
Statin study: 0.9% vs.1.3% (HR 0.68; 95% CI 0.48-0.95)
Bp-lowering study: 1.0% vs. 1.2% (HR 0.86, 95% CI 0.62-1.21)
Statin/BP study: 0.8% vs. 1.4% (HR 0.59; 95% CI 0.37-0.95)
Heart Failure
Statin study: 0.3% vs. 0.5% (HR 0.72; 95% CI 0.41-1.26)
Bp-lowering study: 0.3% vs. 0.5% (HR 0.72; 95% CI 0.41-1.27)
Statin/BP study: 0.3% vs. 0.6% (HR 0.55; 95% CI 0.25-1.19)
Angina with objective evidence of ischemia
Statin study: 0.9% vs. 1.0% (HR 0.87; 95% CI 0.61-1.24)
Bp-lowering study: 0.8% vs. 1.1% (HR 0.74; 95% CI 0.51-1.06)
Statin/BP study: 0.8% vs. 1.2% (HR 0.65; 95% CI 0.39-1.08)

Subgroup Analyses

Statin Study
Benefits remained consistent across baseline cardiovascular risk, LDL, BP, and CRP levels
No heterogeneity by sex, age, race or ethnic group
BP Study (By Thirds of Baseline SBP)
Trend towards co-primary outcome (P=0.02), second co-primary outcome (P=0.009), first secondary outcome (P=0.005)
No trend towards stroke differences (P=0.22)
Patients in the upper third of baseline SBP, compared to placebo had a nominally significant reduction of the first coprimary outcome (HR 0.73), secondary coprimary outcome (HR 0.76), and first seocndary outcome (HR 0.72)
No interactions among baseline risk, LDL, diastolic BP
Combination Study
No significant interactions by stroke risk, LDL, sBP
No heterogeneity in effects by age, sex, race or ethnic group
Statin-only vs. BP-lowering arm: nonsignificant trend towards lower risk of first coprimary outcome (3.8% vs. 4.6%, HR 0.82; 95% CI 0.65-1.05, P=0.11), and marginally significant for second coprimary outcome (4.4% vs. 5.5%, HR 0.79, 95% CI 0.64-0.99, P=0.04)

Other Outcomes, Statin Study

Coronary Heart Disease
1.7% vs. 2.2% (HR 0.74; 95% CI 0.58-0.96; P=0.02)
Total # of second primary outcome events
353 vs. 473 events (HR 0.75; 95% CI 0.64-0.89; P=0.001)
Hospitalizations, cardiovascular causes
4.4% vs. 5.8% (HR 0.75; 95% CI 0.64-0.88; P<0.001)

There was no significant difference between all-cause mortality, new-onset diabetes, or hospitalizations from non-cardiovascular causes.

Other Outcomes, BP-Lowering Study

There was no significant difference between all-cause mortality, new-onset diabetes, hospitalizations from cardiovascular causes, or total # of events (380 vs. 446, HR 0.87, 95% CI 0.74-1.02, p=0.09).

Other Outcomes, BP/Statin Study

Total # of second primary outcome events
169 vs. 262 events (HR 0.66; 95% CI 0.52-0.84; P=0.001)
Hospitalizations from cardiovascular causes
4.4% vs. 6.0% (HR 0.73; 95% CI 0.59-0.91; P=0.005)

There was no significant difference between all-cause mortality, new-onset diabetes, or hospitalization from non-cardiovascular causes.

Adverse Events

BP Study
Discontinuation rates: 24.4% vs. 25.2%
Symptomatic hypotension, lightheadedness, dizziness: 3.4% vs. 2.1% (P<0.001)
Syncope: p=NS
Renal dysfunction: 0.5% vs. 0.3% (p=0.13)
Lipid Study
Discontinuation rates:
Discontinuation because of muscle symptoms: 1.3% vs. 1.2%
Muscle pain or weakness: 5.8% vs. 4.7% (p=0.005)
Rhabdomyolysis: 2 vs. 2
Myopathy: 1 vs. 1
Cataract surgery: 3.8% vs. 3.1% (p=0.02)
VTE: 14 vs. 31 (p=0.01)
Combination Study
Discontinuation rates: 26.3% vs. 28.8%

Criticisms

  • Authors claim 40% reduction in coprimary endpoints in patients with combined treatment with a higher baseline blood pressure (upper 1/3) compared only 20% in those with a lower baseline (lower 2/3); this is based on a post-hoc analysis of which details are not available except for in the study discussion

Funding

  • AstraZeneca (Atacand - Candesartan/HCTZ, Crestor - rosuvastatin) had a single voting member present on a 24-member steering committee
  • Canadian Institutes of Health Research (CIHR)

Further Reading