Heart Outcomes Prevention Evaluation–3 - HOPE-3

Contribution To Literature:

The HOPE-3 trial showed that fixed-dose treatment with low-dose statin therapy, but not BP agents, is superior to placebo in reducing long-term CV events in an intermediate-risk population; the combination group with benefits similar to the statin arm.

Description:

The goal of the trial was to assess the safety and efficacy of cholesterol lowering, blood pressure (BP) lowering, or both in patients without known cardiovascular disease (CVD), and with an intermediate risk of major CV events (~1% annually).

Study Design

Following a 4-week run-in phase with active treatment in all eligible patients, 12,705 patients were randomized in a 2 x 2 factorial design to either (all randomizations were done in a 1:1 fashion):

  1. Cholesterol lowering with rosuvastatin 10 mg (n = 6,361) or placebo (n = 6,344)
  2. BP lowering with candesartan at a dose of 16 mg per day + hydrochlorothiazide (HTCZ) at a dose of 12.5 mg per day (n = 6,356) or placebo (n = 6,349)
  3. Cholesterol and BP lowering with rosuvastatin + candesartan + HCTZ (n = 3,180) or placebo (n = 3,168)

Inclusion criteria:

  • Men ≥55 years, women ≥65 years
  • With at least one of the following CV risk factors:
    • Elevated waist-to-hip ratio
    • History of a low level of high-density lipoprotein cholesterol
    • Current or recent tobacco use, dysglycemia
    • Family history of premature coronary disease
    • Mild renal dysfunction
  • Women with at least two of the above risk factors

Exclusion criteria:

  • Participants with CVD
  • Indication for or contraindication to statins, angiotensin-receptor blockers, angiotensin-converting enzyme inhibitors, or thiazide diuretics
  • Number screened: 14,682
  • Total number of enrollees: 12,705
  • Duration of follow-up: 5.6 years
  • Mean patient age: 65.8 years
  • Percentage female: 46%

Other salient features/characteristics:

  • Elevated waist-to-hip ratio: 87%, low high-density lipoprotein (HDL): 36%, impaired fasting glucose or glucose tolerance: 13%, early diabetes mellitus: 6%
  • Presence of two risk factors: 47%, presence of ≥3 risk factors: 24%
  • BP at baseline: 138/82 mm Hg
  • Low-density lipoprotein cholesterol (LDL-C): 128 mg/dl, HDL-C: 45 mg/dl, triglycerides: 127 mg/dl
  • Ethnicity: Chinese: 29%, Hispanic: 27%, White 20%, South Asian: 15%, Black: 2%
  • Aspirin: 11%

Principal Findings:

1. Cholesterol Lowering:

First co-primary endpoint: Composite of CV death/myocardial infarction (MI)/stroke for rosuvastatin vs. placebo: 3.7% vs. 4.8%, hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.64-0.91, p = 0.002, number needed to treat (NNT) = 91

Second co-primary outcome: Composite of CV death/MI/stroke/resuscitated cardiac arrest/heart failure/revascularization: 4.4% vs. 5.7%, HR 0.75, 95% CI 0.64-0.88, p < 0.001

Secondary outcomes:

  • MI: 0.7% vs. 1.1%, p > 0.05
  • Coronary artery disease (CAD): 1.7% vs. 2.2%, p = 0.02
  • Hospitalization for CV causes: 4.4% vs. 5.8%, p < 0.001
  • New-onset diabetes mellitus: 3.9% vs. 3.8%, p = 0.82
  • LDL-C 39.6 mg/dl lower in the rosuvastatin group than in the placebo group at 1 year, 34.7 mg/dl lower at 3 years, and 29.5 mg/dl lower at the end of the trial (overall mean difference, 34.6 mg/dl or 26.5%; p < 0.001)

2. BP Lowering:

First co-primary endpoint: Composite of CV death/MI/stroke for candesartan + HCTZ vs. placebo: 4.1% vs. 4.4%, HR 0.93, 95% CI 0.79-1.1, p = 0.40

Second co-primary outcome: Composite of CV death/MI/stroke/resuscitated cardiac arrest/heart failure/revascularization: 4.9% vs. 5.2%, p = 0.51

There was a significant interaction with systolic BP (SBP), such that patients with SBP >143.5 mm Hg had a significant reduction in both co-primary endpoints (p = 0.02 and 0.009, respectively) in the active arm.

Secondary outcomes:

  • All strokes: 1.2% vs. 1.5%, p = 0.14
  • MI: 0.8% vs. 1.0%, p = 0.34
  • Hospitalization for CV causes: 5.0% vs. 5.2%, p = 0.63
  • Average differences in SBP/diastolic BP (DBP) between the two arms: 6.0/3.0 mm Hg
  • Symptomatic hypotension: 3.4% vs. 2.0%, p < 0.001

3. Combined Cholesterol and BP Lowering:

First co-primary endpoint: Composite of CV death/MI/stroke for rosuvastatin + candesartan + HCTZ vs. placebo: 3.6% vs. 5.0%, HR 0.71, 95% CI 0.56-0.9, p = 0.005; NNT = 72

Second co-primary outcome: Composite of CV death/MI/stroke/resuscitated cardiac arrest/heart failure/revascularization: 4.6% vs. 6.5%, p = 0.001

Secondary outcomes:

  • CV death: 2.4% vs. 2.9%, p > 0.05
  • All strokes: 1.0% vs. 1.7%, p < 0.05
  • MI: 0.7% vs. 1.2%, p < 0.05
  • Hospitalization for CV causes: 4.4% vs. 6.0%, p = 0.005
  • Average differences in SBP/DBP between the two arms: 6.2/3.2 mm Hg
  • Mean LDL-C level was lower by 33.7 mg/dl; p < 0.001

Effect on cognitive function: Assessed in patients ≥70 years (available n = 1,626). Median age 74 years; 59% female. Cognitive decline was noted in all patients. The primary outcome, processing speed (measured by Digit Symbol Substitution Test [DSST] at study end) for rosuvastatin vs. placebo: 29.1 vs. 29.4 (p = 0.38); for BP lowering vs. placebo: 29.1 vs. 29.4 (p = 0.86); for combination vs. placebo: 29.3 vs. 29.9 (p = 0.63). Any functional impairment for rosuvastatin vs. placebo: 57% vs. 59%, p = 0.89; for BP lowering vs. placebo: 59% vs. 56%, p = 0.19.

Interpretation:

The results of this trial indicate that the use of low-dose statin therapy with rosuvastatin 10 mg is superior to placebo in reducing long-term CV events in an intermediate-risk population (CV event rate ~1%/year). On the other hand, a fixed-dose combination of candesartan 16 mg + HCTZ 12.5 mg daily was not superior to placebo in reducing CV events despite a 6 mm decrease in SBP and a 3 mm decrease in DBP. There was effect modification by baseline SBP, such that patients who truly had hypertension (i.e., >143.5 mm Hg) appeared to benefit with combination treatment. A fixed-dose combination of all three drugs appeared to have CV benefits that were mostly similar to those observed with rosuvastatin compared with placebo. In the subset of patients ≥70 years, there was no signal of differential cognitive decline with all three strategies compared with placebo.

Many features of this trial deserve comment. First, it was designed as a practical trial, with few mandatory visits to titrate medications based on cholesterol or BP response. This might thus lend itself well to a “polypill” approach for large populations, but lowering of LDL-C and/or BP could have been greater if these were periodically assessed and dosages adjusted accordingly, particularly for the BP lowering arm. Second, rather than enrolling patients based on baseline values of LDL-C or BP, they were enrolled based on their baseline risk for CV events. This has been endorsed by the most recent lipid guidelines, and was also recently observed in the SPRINT trial for BP lowering. These results thus provide further validation of the 2015 lipid guidelines approach.

Next, the trial enrolled patients from many different countries, with close to 50% of Asian ethnicity. Since these countries have a progressively larger burden of CVD, these results may be more broadly generalizable. For the BP arm, it is unclear if the use of other agents such as chlorthalidone or amlodipine would have demonstrated a benefit rather than HCTZ/candesartan.

References:

Presented by Dr. Jackie Bosch at the American Heart Association Annual Scientific Sessions (AHA 2016), New Orleans, LA, November 13, 2016.

1. Yusuf S, Bosch J, Dagenais G, et al., on behalf of the HOPE-3 Investigators. Cholesterol Lowering in Intermediate-Risk Persons Without Cardiovascular Disease. N Engl J Med 2016;Apr 2:[Epub ahead of print].

Presented by Dr. Jackie Bosch at the American College of Cardiology Scientific Session, Chicago, IL, April 2, 2016.

2. Lonn EM, Bosch J, Lopez-Jaramillo P, et al., on behalf of the HOPE-3 Investigators. Blood-Pressure Lowering in Intermediate-Risk Persons Without Cardiovascular Disease. N Engl J Med 2016;Apr 2:[Epub ahead of print].

Presented by Dr. Eva M. Lonn at the American College of Cardiology Scientific Session, Chicago, IL, April 2, 2016.

3. Yusuf S, Lonn E, Pais P, et al., on behalf of the HOPE-3 Investigators. Blood-Pressure and Cholesterol Lowering in Persons Without Cardiovascular Disease. N Engl J Med 2016;Apr 2:[Epub ahead of print].

Presented by Dr. Salim Yusuf at the American College of Cardiology Scientific Session, Chicago, IL, April 2, 2016.

Editorial: Cushman WC, Goff DC Jr. More HOPE for Prevention With Statins. N Engl J Med 2016;Apr 2:[Epub ahead of print].

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Clinical Topic Collection: Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Hypertension

Keywords: ACC Annual Scientific Session, AHA Annual Scientific Sessions, Benzimidazoles, Blood Pressure, Cholesterol, LDL, Dyslipidemias, Heart Arrest, Heart Failure, Hydrochlorothiazide, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Hypotension, Lipids, Metabolic Syndrome X, Myocardial Infarction, Primary Prevention, Risk, Stroke, Tetrazoles


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