The HOPE-3 trial was presented earlier this month at the American College of Cardiology Scientific Sessions, and has been published in the New England Journal of Medicine with accompanying editorial this month.

HOPE-3 consisted of three analyses looking at statin and blood pressure treatment in intermediate risk persons without cardiovascular disease (CVD). The study overall was performed as a 2by2 factorial. This trial included a total of 12,705 patients from a diverse range of backgrounds in 21 countries on six continents. The mean total cholesterol level was 5.21 mmol/l and mean LDL-cholesterol was 3.30 mmol/l. The mean blood pressure was 138.1/91.9 mmHg (with 38.9% of the entire population being hypertensive >140mmHg). Approximately half of the participants were women and 80% were non-white with the aim of being able to obtain data that could shape truly international recommendations in the realm of primary prevention for CVD.

The trial included men 55 years or older and women 65 years or older who at least one other CVD risk factor [elevated waist-to-hip ration; history of low level of HDL cholesterol; current or recent positive smoking status; dysglycaemia; family history or premature of coronary artery disease; and mild renal dysfunction]. Women 60 years or older with two risk factors were also included. It is important to note that no absolute level of cholesterol or blood pressure was used as an inclusion or exclusion criteria.

All cardiovascular events and cases of new-onset diabetes were documented and adjudicated. The first co-primary outcome was the composite of death from cardiovascular causes, non-fatal myocardial infarction (MI), or non-fatal stroke (CVA). The second coprimary outcome included all of the above plus resuscitated cardiac arrest, heart failure, and revasularization. The secondary outcome was the second co-primary outcome plus angina with evidence of ischaemia.

In the first analyses,1 the study looked at blood-pressure treatment with combination treatment [candesartan 16mg/daily – hydrochlorothiazide 12.5mg/daily] compared to placebo. The average blood pressure of the participants at baseline was 138.1/81.9mmHg, and there was an average reduction of 6mmHg over the course of the trial. The authors reported that the blood-pressure treatment group did not have significantly different rates of a composite of CV-death, nonfatal MI, or nonfatal CVA a mean of 5.6 years later compared to placebo [4.1% vs. 4.4%, respectively].1 There were also no significant differences between groups in the second co-primary outcomes, with percentages affected 4.9% vs. 5.2% respectively.1

However, in a pre-specified subgroup analysis, that divided baseline systolic blood pressure into thirds, showed that patients with the upper third measurements (>143.5 mmHg) receiving anti-hypertensive therapy met the coprimary outcomes. The authors noted that patients in the lower third measurements had higher events of adverse effects of therapy without any benefit in CV outcomes which contradicts the “lower is better” hypothesis.1

In the accompanying editorial, it was postulated that higher doses of anti-hypertensive treatment may have seen a reduction in CV events.4 With the patient group as a whole having a high-normal BP, the half-doses appear to have been selected for safety purposes and to avoid excess in medication induced side-effects. Indeed, the authors agree that the study does not exclude the possibility that more effective therapy for BP lowering might be beneficial in a relatively low-risk population.1

In the second analyses, participants were randomized to rosuvastatin 10mg/day compared to placebo.2 The first coprimary outcome occurred in 235 participants (3.7%) in the rosuvastatin group and in 304 participants (4.8%) in the placebo group with the number needed to treat with rosuvastatin to prevent one coprimary out-come event being 91. The overall mean low-density lipoprotein cholesterol level was 26.4% lower in the treatment group, which is in keeping with expected findings for therapy with moderate intensity statin.2 In the rosuvastatin there were no excess in diabetes or cancers, but there was an excess of cataract surgery (3.8% in statin group vs 3.1% in placebo group, p=0.02) and muscle symptoms (5.8% in statin group vs 4.7% in placebo group, p=0.005).2 However, the overall rate of discontinuation for adverse events was lower among participants who received rosuvastatin 10mg than among those who received placebo.2 It should be noted that the study included a 4-week run in period where all eligible participants entered a single-blind run in phase where they received both active treatments.1-3 Therefore, we should be cautious about drawing conclusions about the low incidence of drug related side effects in this trial.

In the third analyses,3 patients were randomized to rosuvastatin + candesartan/hydrochlorothiazide vs rosuvastatin + placebo vs candesartan/hydrochlorothiazide + placebo vs double placebo. The findings showed that those who received both of the treatment drugs together had significantly lower rates of the first primary outcome vs the double placebo (3.6% vs. 5.0%, respectively, p=0.005), as well as the second primary outcome measure (4.3% vs. 5.9%, p=0.003). Within subgroup analysis the only group who benefit from combination therapy with statin and blood pressure medications, were patients who were hypertensive3. There was not a significant interaction between the two treatments reported.3

It should be noted that the aspirin was not included in the study design, with the authors reporting that this was a study looking at primary prevention trial rather than secondary prevention where the role of aspirin is clear. Furthermore, the role of aspirin in primary prevention is the subject of ongoing debate.

Implications for Practice
The HOPE-3 trial provides evidence to reinforce some current guideline recommendations and to influence future guidelines. The results support a risk-based approach to statin prescription that has been recommended in recent guidelines5-7 rather than an approach based primarily on specific levels of LDL. The study also supports the use of statin treatment as a safe and effective intervention for primary risk prevention for patients at intermediate risk of developing cardiovascular disease with number needed to treat of 91.

In the USA ACC/AHA guidelines recommend the consideration of treatment with a moderate to high intensity statin for patients with a 10-year risk of 7.5% or higher,7 with the UK recently revising down the threshold for starting preventative treatment for cardiovascular disease (CVD) from a 20% risk of developing CVD within 10 years to patients with a 10% risk5-6. Indeed, the HOPE-3 study appears to vindicate these recommendations.

Furthermore, the HOPE-3 study reinforces that current BP target of a systolic of 140mmHg appears to be an acceptable limit for therapeutic intervention, and treating normotensive patients at intermediate risk of CVD provides no benefit. Current UK guidelines propose recommended targets for treating patients of an ambulatory blood pressure reading of <140/90mmHg for those <80 years old, and <150/90mmHg for people over 80 years old.8

In summary we should treat patients by their overall risk score (Q-Risk or ASSIGN) rather than absolute blood pressure or LDL readings in the intermediate risk context. HOPE-3 suggests that treatment with moderate intensity statin for patients at intermediate risk of developing cardiovascular disease should be discussed between clinician and patient. Furthermore, it confirms that there is no benefit to treating patients with a BP within current targets.

1. Lonn EM, Bosch J, Lopez-Jaramillo P, et al. Blood Pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; DOI:10.1056/NEJMoa1600175
2. Yusuf S, Bosch J, Zhu J, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl Med 2016; DOI:10.1056/ NEJMoa1600176
3. Yusuf S, Lonn E, Prem P, et al. Blood-pressure and cholesterol-lowering in persons without cardiovascular disease. N Engl Med 2016; DOI:10.1056/NEJMoa1600177
4. Cushman WC, Goff DC. More HOPE for prevention with statins. Editorial DOI:10.1056/NEJMe1603504
5. Hughes LD. Cholesterol lowering: the statin controversy. Geriatric Medicine 2: Heart & Diabetes 2014. 44(9): p.11-14
6. National Institute for Health and Clinical Excellence. Lipid modification: cardiovascular risk assessmentand modification of blood lipids for the primary andsecondary prevention of cardiovascular disease (update). London: National Institute for Health andClinical Excellence, 2014.
7. Stone NJ, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013. DOI:10.1161/01.cir.0000437738.63853.7a
8. Hughes LD & Flint R. Hypertension. Geriatric Medicine 2: Heart & Diabetes 2014. 44(4): p.26-32