Clinical trials of intensive versus less intensive control of hypertension: HOPE or HYPE?
Authors: Christina M. Wyatt, Glenn M. Chertow
Journal: Kidney International (2016)

The recently published Heart Outcomes Prevention Evaluation trial (HOPE-3) demonstrated no benefit of lowering blood pressure with candesartan and hydrochlorothiazide in persons at intermediate cardiovascular risk and with adequate blood pressure control as determined by the enrolling physician. The results of Systolic Blood Pressure Intervention Trial (SPRINT) and HOPE-3 highlight the importance of considering differences in study design and patient population when interpreting the results of clinical trials. The recently published Heart Outcomes Prevention Evaluation trial (HOPE-3) demonstrated no benefit of lowering blood pressure with candesartan and hydrochlorothiazide in persons at intermediate cardiovascular risk and with adequate blood pressure control as determined by the enrolling physician. The results of Systolic Blood Pressure Intervention Trial (SPRINT) and HOPE-3 highlight the importance of considering differences in study design and patient population when interpreting the results of clinical trials. In results published in September 2015, the Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated statistically significant and clinically meaningful reductions in a composite cardiovascular endpoint and all-cause mortality with intensive systolic blood pressure control (via investigator-driven use of a broad array of lifestyle and pharmacologic interventions) in persons without diabetes mellitus, no history of stroke or polycystic kidney disease, and those who were otherwise at heightened cardiovascular risk owing to advanced age, clinically overt cardiovascular disease, chronic kidney disease (CKD), and/or an elevated Framingham risk score. Within several months, the Heart Outcomes Prevention Evaluation (HOPE-3) trial demonstrated no significant reduction in 2 coprimary composite cardiovascular endpoints with blood pressure lowering with candesartan and hydrochlorothiazide in persons at intermediate cardiovascular risk. Table 1 shows important differences in the study design and patient population of the 2 trials.Table 1Design and results of the HOPE-3 and SPRINT trialsHOPE-3SPRINTEnrollment criteriaAge ≥ 55 yr (men) or 65 yr (women)Adequate BP control per treating physicianIncreased cardiovascular risk:•Family history of premature CAD•CKD (microalbuminuria, eGFR 45–59 ml/min/1.73 m2, creatinine 1.4–2.0 mg/dL)•Elevated waist: hip ratio•Current/recent smoker•Low HDL cholesterol•Abnormal fasting glucose or glucose tolerance, including diet-controlled diabetesMajor exclusions:•Established cardiovascular disease•Diabetes requiring medication•Clear indications for/contraindications to statin, ACE/ARB, or thiazideAge ≥ 50 yrSystolic BP 130–180 mm HgIncreased cardiovascular risk:•Established cardiovascular disease•CKD (eGFR 20–59 ml/min/1.73 m2)•Framingham risk ≥ 15%•Age ≥ 75 yrMajor exclusions:•Prior stroke•DiabetesInterventionCandesartan/HCTZ 16/12.5 mg versus placeboSystolic BP target < 120 versus < 140 mm HgSpecifiedBP measureAttended automated BP measurement; average of 2 seated measures at least 1 min apartUnattended automated BP measurement; average of 3 seated measures 5 min apartAchieved BP differenceaAverage difference in systolic blood pressure between treatment groups over the course of the trial.6 mm Hg13 mm HgFollow-up5.6 yr3.3 yrPrimary outcome(i)Composite of cardiovascular death, nonfatal MI, and nonfatal stroke(ii)Composite of the above plus resuscitated cardiac arrest, heart failure, or revascularizationComposite of cardiovascular death, nonfatal MI or acute coronary syndrome, nonfatal stroke, or decompensated heart failureEvent rate(i)Cumulative incidence 4.1% versus 4.4%(ii)Cumulative incidence 4.9% versus 5.2%Annual incidence 1.65% versus 2.19%Treatment effect(i)HR 0.93; 95% CI, 0.79–1.10(ii)HR 0.95; 95% CI 0.81–1.11HR 0.75; 95% CI 0.64–0.89ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CAD, coronary artery disease; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HCTZ, hydrochlorothiazide; HDL, high-density lipoprotein; HOPE-3, Heart Outcomes Prevention Evaluation; HR, hazard ratio; MI, myocardial infarction; SPRINT, Systolic Blood Pressure Intervention Trial.a Average difference in systolic blood pressure between treatment groups over the course of the trial. Open table in a new tab ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CAD, coronary artery disease; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HCTZ, hydrochlorothiazide; HDL, high-density lipoprotein; HOPE-3, Heart Outcomes Prevention Evaluation; HR, hazard ratio; MI, myocardial infarction; SPRINT, Systolic Blood Pressure Intervention Trial. SPRINT enrolled 9361 adults with at least one criterion of increased risk for cardiovascular events, including established cardiovascular disease or CKD, and with systolic blood pressure 130 to 180 mm Hg.1The SPRINT Research GroupA randomized trial of intensive versus standard blood pressure control.N Engl J Med. 2015; 373: 2103-2116Crossref PubMed Scopus (3909) Google Scholar Participants were randomized to intensive blood pressure control (target systolic blood pressure < 120 mm Hg) versus routine blood pressure control (target systolic blood pressure < 140 mm Hg). Over a median follow-up of 3.3 years, the risk of cardiovascular events (a composite endpoint of cardiovascular death or nonfatal myocardial infarction or stroke) was significantly reduced in participants randomized to intensive systolic blood pressure control. SPRINT results were reviewed in detail in a previous Nephrology Digest.2Rocco M.V. Cheung A.K. A SPRINT to the finish, or just the beginning? Implications of the SPRINT results for nephrologists.Kidney Int. 2016; 89: 261-263Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar HOPE-3 enrolled 12,705 adults with at least one criterion for increased cardiovascular risk, no documented cardiovascular disease, and adequate blood pressure control as determined by the enrolling investigator.3Lonn E.M. Bosch J. Lopez-Jaramillo P. et al.HOPE-3 Investigators. Blood pressure lowering in intermediate-risk persons without cardiovascular disease.N Engl J Med. 2016; 374: 2009-2020Crossref PubMed Scopus (447) Google Scholar Participants were randomized to a fixed-dose combination of candesartan and hydrochlorothiazide versus placebo, with no specified blood pressure target. Blood pressure decreased in both study groups during the trial, with a mean difference in achieved systolic blood pressure of 6 mm Hg between the 2 treatment arms. After a median follow-up of 5.6 years, there was no significant difference in either of the coprimary composite cardiovascular endpoints between the treatment groups. In a prespecified subgroup analysis, a small but statistically significant benefit of antihypertensive therapy was observed in participants with baseline systolic blood pressure in the upper tertile of the baseline distribution (> 143.5 mm Hg). Perhaps the most important difference between SPRINT and HOPE-3 was in participant selection, with patients at variable risk of cardiovascular events.1The SPRINT Research GroupA randomized trial of intensive versus standard blood pressure control.N Engl J Med. 2015; 373: 2103-2116Crossref PubMed Scopus (3909) Google Scholar, 3Lonn E.M. Bosch J. Lopez-Jaramillo P. et al.HOPE-3 Investigators. Blood pressure lowering in intermediate-risk persons without cardiovascular disease.N Engl J Med. 2016; 374: 2009-2020Crossref PubMed Scopus (447) Google Scholar Although documented cardiovascular disease was an exclusion criterion in HOPE-3, approximately 20% of SPRINT participants had known cardiovascular disease at enrollment. Other important differences between the HOPE-3 and SPRINT populations included the prevalence of black race (< 2% vs. 31%, respectively) and baseline use of antihypertensive medications (22% vs. > 90%, respectively). Although CKD was a possible criterion for increased cardiovascular risk in both trials, enrollment of participants with CKD was much lower in HOPE-3 (< 3% vs. 28% in SPRINT), perhaps because CKD might have been considered by enrolling physicians to be an indication for renin angiotensin aldosterone system blockade, violating equipoise. As a result of these and other differences between the study populations, the anticipated and observed cardiovascular event rates were much lower than those in HOPE-3. Another key difference between the trials was in the blood pressure intervention itself. Unlike SPRINT, the intensive control arm of HOPE-3 did not include dose titration toward a specific blood pressure target. In addition, all participants in HOPE-3 had baseline blood pressures that were considered acceptable by the enrolling investigator, whereas SPRINT allowed baseline systolic blood pressures as high as 180 mm Hg. As a result of these differences in study design, the achieved difference in blood pressure between treatment arms was much smaller in HOPE-3 than in SPRINT, with a mean difference between groups in systolic blood pressure of approximately 6 mm Hg and 13 mm Hg over the course of the trials, respectively. Another important difference between HOPE-3 and SPRINT was in the protocol for blood pressure measurement. Both trials used the same automated blood pressure measurement system; however, the SPRINT protocol specified that measurements be taken unattended, with no study personnel in the room.1The SPRINT Research GroupA randomized trial of intensive versus standard blood pressure control.N Engl J Med. 2015; 373: 2103-2116Crossref PubMed Scopus (3909) Google Scholar, 4Kjeldsen S.E. Lund-Johansen P. Nilsson P.M. Mancia G. Unattended Blood Pressure Measurements in the Systolic Blood Pressure Intervention Trial. Implications for entry and achieved blood pressure values compared with other trials.Hypertension. 2016; 67: 808-812Crossref PubMed Scopus (169) Google Scholar The extent to which unattended measurements in a clinical setting reduce the "white coat effect" is not well studied, but it seems likely to yield results intermediate to routine clinic blood pressures and ambulatory blood pressure monitoring. Although the specified method of measuring blood pressure should not have biased the observed difference in blood pressure (or endpoints) between the randomized treatment arms in SPRINT, it is unclear whether the achieved blood pressures can be directly compared with those in other large randomized trials or in clinical practice, where blood pressure measurements are typically taken in the presence of study personnel or clinic staff.5Hansson L. Zanchetti A. Carruthers S.G. et al.Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group.Lancet. 1998; 351: 1755-1762Abstract Full Text Full Text PDF PubMed Scopus (5425) Google Scholar, 6The ACCORD Study GroupEffects of intensive blood-pressure control in type 2 diabetes mellitus.N Engl J Med. 2010; 362: 1575-1585Crossref PubMed Scopus (2738) Google Scholar So, how will (or should) these results inform (or change) clinical practice? For nephrologists, it is unclear whether the results of HOPE-3 apply to patients with CKD, who made up less than 3% of the study population and who may be at higher risk of cardiovascular events than the included participants.7Tonelli M. Muntner P. Lloyd A. et al.for the Alberta Kidney Disease NetworkRisk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study.Lancet. 2012; 380: 807-814Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar In contrast, there was no significant interaction between CKD status and treatment assignment in SPRINT, suggesting that the observed benefits of intensive blood pressure control do indeed extend to patients with CKD.1The SPRINT Research GroupA randomized trial of intensive versus standard blood pressure control.N Engl J Med. 2015; 373: 2103-2116Crossref PubMed Scopus (3909) Google Scholar The Joint National Commission 8 (JNC-8) guidelines recommend a blood pressure < 140/90 mm Hg for adults with CKD,8Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work GroupKDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.Kidney Int. 2012; 2: 337-414Google Scholar whereas the Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend a goal systolic blood pressure ≤ 130 mm Hg for those with albuminuria.9James P.A. Oparil S. Carter B.L. et al.2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults. Report from the Panel Members Appointed to the Eighth Joint National Committee (JNC 8).JAMA. 2014; 311: 507-520Crossref PubMed Scopus (5848) Google Scholar Both SPRINT and HOPE-3 support the benefits of controlling systolic blood pressure below 140 mm Hg in patients with hypertension and at least one additional cardiovascular risk factor. In patients at higher cardiovascular risk, including those with established cardiovascular disease or CKD, results from SPRINT suggest that more intensive systolic blood pressure control such as that recommended in the KDIGO guidelines is likely to reduce the risk of death or cardiovascular events. All the authors declared no competing interests.