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Macrovascular Residual Risk THROUGH LANDMARK STUDY

8 December 2015
SPRINT: Benefits of intensive blood pressure control

SPRINT showed significant benefit associated with intensive blood pressure control (<120 mmHg systolic blood pressure [SBP]) in patients at high cardiovascular risk but without diabetes

The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Eng J Med 2015; Epub 9th November 2015
Summary
Comments & References
STUDY SUMMARY
Objective: To investigate whether a lower SBP goal (<120 mmHg) would reduce clinical events more than the standard goal of <140 mmHg in non-diabetic patients at high risk of cardiovascular events.
Study design: Randomized, controlled, open-label multicentre trial. Eligible patients were randomly allocated to a SBP treatment target of <120 mmHg or <140 mmHg. Baseline antihypertensive regimens were adjusted on the basis of this allocation. Patients were seen monthly for the first 3 months and every 3 months thereafter.
Study population: 9,361 high-risk cardiovascular patients ≥50 years (mean 67.9 ± 9.4 years, 36% female, 57.7% non-Hispanic white) with SBP ≥130 mm Hg (130 to 180 mmHg).  Baseline SBP was 139.7 ± 15.4 mmHg (34% with SBP ≥145 mmHg).  Overall, 20% had evidence of cardiovascular disease. Concomitant cardiovascular medication was similar in the two groups; 42-44% were receiving a statin and 50-51% were on aspirin.
Primary efficacity measures: A composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes
Secondary efficacity measures:

-        Individual components of the primary composite outcome

-        death from any cause

-        composite of the primary outcome or death from any cause

-        renal outcomes: composite of ≥50% decrease in the estimated glomerular filtration (eGFR) rate, or development of end-stage renal disease requiring long-term dialysis or kidney transplantation (patients with chronic kidney disease at baseline); ≥30% decrease in eGFR to <60 ml/minute/1.73 m2 (patients without chronic kidney disease at baseline).

-        Incident albuminuria

Methods: A mean 5-year follow-up period was planned. The primary analysis was an intention-to-treat (ITT) analysis of the time to the first occurrence of a primary outcome using Cox proportional-hazards regression with two-sided tests at the 5% level of significance.
Main results:
  • At 1 year mean SBP was 121.4 mmHg in the intensive treatment group versus 136.2 mmHg in the standard treatment group.
  • The trial was stopped early subsequent to recommendations of the Data Safety and Monitoring Committee after a median follow-up of 3.26 years due to significant decrease in the primary composite outcome, and all-cause and cardiovascular death in the intensive-treatment group compared with standard-treatment group (Table 1). There was no significant impact on stroke.

Table 1. Key study outcomes, n (%)

Outcome

Intensive SBP control (n=4,678)

Standard SBP control (n=4,683)

Hazard ratio             (95% CI)

Primary

243 (5.2)

319 (6.8)

0.75 (0.64–0.89)**

Secondary

 

 

 

Cardiovascular death

37 (0.8)

65 (1.4)

0.57 (0.38–0.85)*

All-cause death

155 (3.3)

210 (4.5)

0.73 (0.60–0.90)*

Primary outcome or death

332 (7.1)

423 (9.0)

0.78 (0.67–0.90)**

Heart failure

62 (1.3)

100 (2.1)

0.62 (0.45–0.84)**

*p≤0.005; **p<0.001

  • In patients without chronic kidney disease at baseline, intensive blood pressure lowering led to more than 3-fold increase in patients with a decrease in eGFR ≥30% to <60 ml/min/1.73 m2 (3.8% versus 1.1% on standard treatment, p<0.001).
  • Intensive blood pressure control was also associated with significant increases in serious adverse events including hypotension, syncope, electrolyte abnormality, and acute kidney injury or acute renal failure. There was, however, no significant difference between the groups for the incidence of injurious falls.
Authors’ conclusion: Among patients at high risk for cardiovascular events but without diabetes, targeting a SBP of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group.

COMMENT

Whether intensive blood pressure lowering is associated with significantly greater benefit on clinical outcomes has been much debated. The previous Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (1) investigated this issue in high cardiovascular risk patients with type 2 diabetes, but showed no significant benefit on cardiovascular outcomes (reduction by 12%) with intensification of blood pressure control. There was, however, a significant decrease in stroke, although the number of events was small and hence confidence interval was wide (Hazard ratio 0.59, 95% CI 0.39-0.89, p=0.01), with a 5-year NNT elevated.

The findings from SPRINT, a much larger, adequately powered trial, change the perspective on blood pressure targets, albeit in high-risk patients without diabetes. The obvious question is what to do in patients with type 2 diabetes? Returning to the ACCORD study (1), it should be noted that the 95% confidence interval for the 12% decrease in major cardiovascular events includes the possibility of a 27% lower risk of major cardiovascular outcomes, consistent with the benefit observed in SPRINT. Furthermore, follow-up data from the ACCORD trial, presented at the American Heart Association Scientific Sessions this year (2) provide more insights. Over a median follow-up of 8.8 years, the group allocated to intensive blood pressure lowering did not have a lower rate of the composite endpoint of nonfatal myocardial infarction or stroke or cardiovascular death (annual event rate 2.03% in the intensive group and 2.22% in the standard group, hazard ratio 0.91, 95% CI 0.79 to 1.05, p=0.19). However, the possibility of an interaction between glycaemic and blood pressure control suggested in the ACCORD trial was confirmed in the follow-up data (p for interaction =0.037) (2). Taking this into account, there was a 21% reduction in major cardiovascular events in type 2 diabetes patients allocated to intensive blood pressure control in the standard glycaemic arm (hazard ratio 0.79, 95% CI 0.65–0.96). Although these findings should be regarded as hypothesis-generating and not definitive, the magnitude of benefit is consistent with that observed in SPRINT.

Any change in therapeutic management needs to consider the benefit versus risk profile of the treatment. In SPRINT, intensive blood pressure control was also associated with significant increases in serious adverse events including hypotension, syncope, electrolyte abnormality, and acute kidney injury or acute renal failure. Thus these adverse events need to be weighed against the potential for clinical outcomes benefit with this approach. Additionally, there are practical considerations, as attainment of this lower SBP goal (<120 mmHg) is likely to be particularly challenging in routine practice. Already EUROASPIRE IV has shown that less than 50% of secondary prevention patients attain a blood pressure target of <140/90 mmHg (3); similar findings were reported in ASPIRE-2-PREVENT in patients with coronary heart disease and those at high risk of developing cardiovascular disease (4).

Probably the take home message from SPRINT is that attaining a lower SBP than recommended by current guidelines has clinical benefit in older adults at high cardiovascular risk without diabetes, although the benefit versus risk profile needs to be taken into account. For high risk patients with type 2 diabetes, follow-up data from ACCORD suggest possible benefit in further lowering SBP, in association with recommended standard glycaemic management, to reduce residual cardiovascular risk beyond standard care alone.

References

1. ACCORD Study Group, Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.

2. Cushman WC, Evans GW, Cutler JA; ACCORD/ACCORDION Study Group. Long-term cardiovascular effects of 4.9 years of intensive blood pressure control in type 2 diabetes mellitus: The Action to Control Cardiovascular Risk in Diabetes Follow-On Blood Pressure Study. AHA Scientific Sessions 2015.  

3. Kotseva K, Wood D, De Bacquer D, et al. EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries. Eur J Prevent Cardiol 2015; Epub ahead of print.

4. Kotseva K, Jennings CS, Turner EL, Mead A, Connolly S, Jones J, Bowker TJ, Wood DA; ASPIRE-2-PREVENT Study Group. ASPIRE-2-PREVENT: a survey of lifestyle, risk factor management and cardioprotective medication in patients with coronary heart disease and people at high risk of developing cardiovascular disease in the UK. Heart 2012;98:865-71.

Key words high cardiovascular risk; all-cause mortality, cardiovascular mortality; intensive blood pressure control; ACCORD; residual cardiovascular risk