HOPE-3: Blood Pressure Lowering Alone Fails to Deliver For Some

No role for antihypertensives in non-hypertensive primary prevention?

The polypill concept - a single pill combining an antihypertensive with a lipid lowering agent for universal primary prevention of cardiovascular disease - hit a speed bump in HOPE-3 with evidence that lowering blood pressure does not guarantee fewer heart attacks and strokes for all regardless of baseline blood pressure.

HOPE-3 did not deliver blood pressure and lipid-lowering drugs in a single pill, but Salim Yusuf, MBBS, of McMaster University in Hamilton, Ontario, who was senior author of the HOPE-3 reports, said the study was the first formal testing of the polypill concept on clinical events. The study tested the concept in intermediate risk patients without pre-existing cardiovascular disease.

Three treatments arms were tested in the trial: 16 mg candesartan plus 12.5 hydrochlorothiazide (Atacand), the blood pressure combination plus 10 mg rosuvastatin (Crestor), and rosuvastatin alone. Each treatment was compared with placebo.

After a median of 5.6 years, the risk of cardiovascular death, nonfatal MI, or nonfatal stroke was 4.1% versus 4.4%, (hazard ratio 0.93, P=0.40). The results were published online in the New England Journal of Medicine.

Including resuscitated cardiac arrest, heart failure, and revascularization events along with the hard endpoints in a second co-primary composite endpoint likewise showed no advantage to blood pressure-lowering treatment (4.9% versus 5.2% on placebo, HR 0.95, P=0.51).

"The overall null results of the blood-pressure-lowering component of HOPE-3 could be due to insufficient dosing of antihypertensive medications, treatment of a relatively low-risk group, or chance," William C. Cushman, MD, and David C. Goff, Jr., MD, PhD, in an editorial in NEJM.

"If higher doses had been used, the risk of cardiovascular events might have been significantly reduced, whether from greater blood-pressure lowering, additional effects of the antihypertensive drugs, or both," Cushman and Goff added.

There was one prespecified subgroup that did appear to benefit -- people with the highest baseline blood pressures, above 143.5 mm Hg, which would put them in line for antihypertensive treatment under current guidelines.

In that group only, antihypertensive treatment reduced risk of both co-primary composite endpoints (P=0.02 and P=0.009, respectively, for trend in the two outcomes).

Neither benefit nor harm was seen in the lower baseline blood pressure tertiles, although the lowest tertile group had a "possible trend for harm" with a nonsignificant hazard ratio of 1.16 for the composite of cardiovascular death, MI, or stroke (95% CI 0.82-1.63).

Despite the hypothesis generating nature of this subgroup finding, the researchers cautioned against ignoring it.

Both lipid only and lipid plus blood pressure medicine arms did demonstrate a benefit -- although the absolute benefit was less than 2%. The trial was presented as a late-breaking clinical trial at the American College of Cardiology meeting and during a press conference there, Yusuf said the evidence suggests that blood pressure must be monitored, while checking LDL levels is not necessary with statin therapy.

The editorialists were less ready to give up on the concept. “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,” they wrote. “However, these results do not rule out the possibility of a benefit with longer-term treatment in a portion of this relatively low-risk population.”

For the blood pressure arm, the trial enrolled 12,705 participants at intermediate risk who did not have cardiovascular disease and randomized them to 16-mg candesartan plus 12.5-mg hydrochlorothiazide per day or placebo.

The mean baseline blood pressure was 138.1/81.9 mm Hg, and this declined by 6.0/3.0 mm Hg more with treatment than with placebo.

That editorialists noted that the 95% confidence interval for benefit did not exclude the magnitude of an effect one might expect from this small differential in blood pressure.

Most antihypertensive trials have used higher-risk populations to boost trial efficiency and demonstrated cardiovascular benefit for lowering blood pressure in people with an average systolic above 130 mm Hg and either known cardiovascular disease or predicted 5-year risk of cardiovascular events of at least 6.5%, Cushman and Goff noted. In SPRINT, people without baseline cardiovascular disease had to have either subclinical cardiovascular disease or 10-year cardiovascular risk of more than 15%.

last updated 04.07.2016

Primary Source: Lonn EM, et al "Blood-pressure lowering in intermediate- risk persons without cardiovascular disease" N Engl J Med 2016; DOI: 10.1056/NEJMoa1600175.

Secondary Source: Cushman WC, et al "More HOPE for prevention with statins" N Engl J Med 2016; DOI: 10.1056/NEJMe1603504.

This article was first published on MedPage Today and reprinted with permission from UBM Medica. Free registration is required.

Disclosures:

The trial was funded by the Canadian Institutes of Health Research and AstraZeneca.

Lonn disclosed relationships with both those organizations and Bayer, GlaxoSmithKline, Merck Schering, Eli Lilly, Amgen, Sanofi, and Novartis.

Cushman reported grant support from Merck and Eli Lilly outside the submitted work. He is also an uncompensated member of the steering committee for the Takeda-sponsored EXAMINE diabetes CV outcome trial, and he provides uncompensated consulting to Takeda related to hypertension clinical trials.