HOPE-3: Blood Pressure and Cholesterol Lowering in Immediate-Risk Patients Without CVD

Results from HOPE-3 suggest statins can be more widely used in intermediate-risk patients without cardiovascular disease.

Blood pressure and cholesterol-lowering effects were studied in patients without the presence of cardiovascular (CV) disease but who were considered “immediate risk” for disease in the HOPE-3 (Heart Outcomes Prevention Evaluation) clinical trial.

The findings were presented by study investigators Eva Lonn, MD, MSc, FRCPC, FACC; Jackie Bosch, MD; and Salim Yusuf, MD, DPhil at the 2016 American College of Cardiology Scientific Sessions & Expo (ACC) in Chicago and simultaneously published in the New England Journal of Medicine.

A total of 12 705 patients were enrolled in the trial with a 2-by-2 factorial design. Patients were recruited from 228 centers in 21 countries and were followed-up for a median of 5.6 years. Dr Eva Lonn, professor of medicine at McMaster University in Hamilton, Canada, pointed out that the ethnically diverse population allowed the research team to conduct multiple subanalyses, including stroke risk, low-density lipoprotein cholesterol (LDL-C) levels, and systolic blood pressure (SBP) values at baseline.

The first coprimary outcome was composite death from CV causes, nonfatal myocardial infarction (MI), or nonfatal stroke.  The second coprimary outcome included resuscitated cardiac arrest, heart failure, and revascularization.

The mean blood pressure was 138.1/81.9 mm Hg at baseline. In addition, the mean SBP was 138.2 ± 14.7 mm Hg in the active-treatment group and 137.9 ± 14.8 mm Hg in the placebo group. The decrease was 6.0/3.0 mm Hg greater in the treatment group vs the placebo group.

Antihypertensive therapy with candesartan (16 mg/day) plus hydrochlorothiazide (HCTZ; 12.5 mg/day) was not associated with lower rates of major CV events compared with placebo. However, researchers did observe significantly lower rates of the first and second coprimary outcomes in the upper third SBP group (>143.5 mm Hg). In the middle and lower thirds, the effects were neutral (P=.02 and P=.009, respectively, for trend in the 2 outcomes).

“The pattern for stroke differed, with no heterogeneity in the 3 subgroups that were defined according to baseline [SBP],” the researchers wrote in 1 of their published reports. “Blood-pressure differences between the trial groups were similar across the 3 subgroups of baseline SBP. Therefore, the observed subgroup findings are not related to differences in the magnitude of blood-pressuring lowering but rather to a differential effect in participants at different baseline blood-pressure levels.”

At the ACC press conference, Dr Lonn commented that both the JNC-8 and European guidelines still debate over the BP entry level for patients with “uncomplicated hypertension,” but the results from HOPE-3 may help better define those values.

By studying the effects of rosuvastatin (10 mg/day) on LDL-C, researchers found that the agent resulted in a significantly lower risk of CV events. The first coprimary outcome occurred in 235 patients (3.7%) of the treatment group and 304 patients (4.8%) in the placebo group (hazard ratio: 0.76; 95% confidence interval: 0.64-0.91; P=.002). Interestingly, results were consistent regardless of race or ethnic group, lipid level, C-reactive protein level, BP, or CV risk at baseline.

Dr Salim Yusuf, president of the World Heart Federation, was careful to note that trials lasting 5 to 6 years, such as HOPE-3, often underestimate the benefits of prevention. Over longer periods of time, combining treatments will lead to better risk reduction and more cost-effective healthcare. “If you don’t have to bring [patients] back to re-titrate drugs over and over again, you’re saving money,” Dr Yusuf said. “You’re also saving [the patient] in indirect ways—time, travel, etc.”

He urged, “We have to simplify prevention. Otherwise, it will not be used widely.”

Valentin Fuster, MD, editor-in-chief of the Journal of the American College of Cardiology, echoed that sentiment. “The future of prevention is no doubt in simplicity,” he remarked at the ACC press conference. “It’s fascinating that you [HOPE-3 investigators] designed such a complex trial to reach simplicity.”  

Dr Yusuf added that although this was the first formal testing of a polypill concept on clinical events, more trials are needed to study the intermediate-risk patient population. 

In an interview with Cardiology Advisor, B. Hadley Wilson, MD, FACC, of the Sanger Heart & Vascular Institute at Carolinas HealthCare System in Charlotte, elaborated on the cost-benefit analysis. “I think we won’t be surprised to see that by reducing these catastrophes in large populations, that we will see a benefit to population health,” he said. “And as we go forward, more studies will be done—maybe even more targeted polypill therapy, if you will, to these high risk populations [to] see if they also benefit over time.”

While the HOPE-3 findings may appear to encourage a “one-size fits all” approach to antihypertensive and lipid-lowering therapy, all 3 investigators insisted that individualized care is paramount.

“Our findings contradict the ‘lower is better’ hypothesis that has been derived from epidemiologic studies and our findings support the concept that a J-curve phenomenon exists for major CV events, other than for stroke, in this population,” the researchers concluded in 1 of their 3 published reports. “…Our data are compatible with the hypothesis that treating persons without CVD who have a SBP above approximately 140 mm Hg appears to be beneficial, but treatment would not be of benefit and may be even harmful in persons with lower SBP levels.”


  1. Bosch J, HOPE-3 Investigators. Abstract 401-18. Effects of rosuvastatin on cardiovascular disease in moderate risk primary prevention in diverse ethnic groups. Presented at the 65th Annual Scientific Session and Expo of the American College of Cardiology. April 2-4, 2016; Chicago, IL.
  2. Lonn EM, Bosch J, Lopez-Jaramillo P, et al; for the HOPE-3 Investigators. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016. doi: 10.1056/NEJMoa1600175.
  3. Lonn EM, HOPE-3 Investigators. Abstract 401-17. Blood pressure lowering in people at moderate risk. The HOPE-3 trial. Presented at the 65th Annual Scientific Session and Expo of the American College of Cardiology. April 2-4, 2016; Chicago, IL.
  4. Yusuf S, Bosch J, Dagenais G, et al; for the HOPE-3 Investigators. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. doi: 10.1056/NEJMoa1600176.
  5. Yusuf S, HOPE-3 Investigators. Abstract 401-19. Effects of combined lipid and BP-lowering on cardiovascular disease in a moderate risk global primary prevention population. Presented at the 65th Annual Scientific Session and Expo of the American College of Cardiology. April 2-4, 2016; Chicago, IL.
  6. Yusuf S, Lonn E, Pais P, et al; for the HOPE-3 Investigators. Blood-pressure and cholesterol lowering in people without cardiovascular disease. N Engl J Med. doi: 10.1056/NEJMoa1600177.