Eva Lonn (Hamilton Health Sciences and McMaster University, Canada)

Effects of Combined Lipid and BP-Lowering on Cardiovascular Disease in a Moderate Risk Global Primary Prevention Population

Salim Yusuf (Hamilton Health Sciences and McMaster University, Canada)

Effects of Rosuvastatin on Cardiovascular Disease in Moderate Risk Primary Prevention in Diverse Ethnic Groups

Jackie Bosch (Hamilton Health Sciences and McMaster University, Canada)

Presented at ACC 2016

Background

Observational studies in people without cardiovascular (CV) disease show a strong, graded association between blood pressure (BP) above 115/75 mmHg and CV risk. Most BP lowering trials included people with established CV disease, diabetes, renal disease and/or hypertension with end organ damage or in the absence of these conditions those with systolic BP above 160 mmHg. However, most CV events in populations arise from persons without these major risk factors and the role of BP lowering drugs among them is uncertain.
The Heart Outcomes Prevention Evaluation–3 (HOPE-3) trial was a double-blind randomized placebo-controlled trial with a 2- by-2 factorial design which evaluated BP lowering with candesartan/hydrochlorothiazide 16/12.5 mg/day, cholesterol lowering with rosuvastatin 10 mg/day and their combination in a population at moderate CV risk.
The trial included 12,705 people (men ≥55 years and women ≥60 years) in 21 countries on six continents. All participants had at least one known cardiovascular risk factor, such as smoking, an elevated waist-to-hip ratio or a family history of heart disease, but none had been diagnosed with cardiovascular disease. The trial was designed to focus on preventing cardiovascular disease before it starts.

Main results

1. 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% (HR 0.95; 95% CI 0.81-1.11; 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.

2. Cholesterol lowering:

First co-primary endpoint:

• Composite of CV death/MI/stroke for rosuvastatin vs. placebo: 3.7% vs. 4.8%, HR 0.76, 95% CI 0.64-0.91, P=0.002, 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

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 0.56-0.90, 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

Conclusion

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). 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.

Editorial comment [4]: These results may help to define the combined threshold of systolic blood pressure (<140 mm Hg) and cardiovascular risk (<5.0%) below which the use of blood-pressure–lowering medications may not be useful in the short term.

Source

Press release ACC 2016

This study was published simultaneously in N Engl J Med:

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