Achieved diastolic blood pressure and pulse pressure at target systolic blood pressure (120–140 mmHg) and cardiovascular outcomes in high-risk patients: results from ONTARGET and TRANSCEND trials

Michael Böhm¹*, Helmut Schumacher², Koon K. Teo³, Eva Lonn³, Felix Mahfoud¹, Johannes F.E. Mann⁴, Giuseppe Mancia⁵, Josep Redon⁶, Roland Schmieder⁷, Michael Weber⁸, Karen Sliwa⁹, Bryan Williams¹⁰, and Salim Yusuf³

Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany; Statistical Consultant, 55216 Ingelheim, Germany; Population Health Research Institute, McMaster University, Hamilton, ON L8L 2X2, Canada; KfH Kidney Center, 80804 Munich-Schwabing and Department of Nephrology and Hypertension, University Hospital, Friedrich-Alexander University, 91054 Erlangen/Nuremberg, Germany; Istituto Clinico Universitario Policlinico di Monza, Università degli Studi di Milano Bicocca, Piazza dell'Ateneo Nuovo, 1, 20126 Milano MI, Italy; Hypertension Unit, Hospital Clínico Universitario, Av. de Blasco Ibáñez, 13, 46010 València, Spain; Department of Nephrology and Hypertension, University Hospital, Friedrich-Alexander University, 91054 Erlangen/Nuremberg, Germany; Downstate College of Medicine, State University of New York, 450 Clarkson Ave, Brooklyn, NY 11203, USA; Hatter Institute for Cardiovascular Research in Africa & IIDMM, Faculty of Health Sciences, University of Cape Town, Private Bag X3 7935, Observatory, South Africa; and University College London (UCL) Institute of Cardiovascular Science and National Institute for Health Research (NIHR) UCL Hospitals Biomedical Research Centre, 149 Tottenham Court Road, London W1T 7DN, UK

* Corresponding author. Tel: (+49)-6841-16-15031, Fax: (+49)-6841-16-15032, Email: [email protected]

Aims Current guidelines of hypertensive management recommend upper limits for systolic (SBP) and diastolic blood pressure (DBP). J-curve associations of BP with risk exist for some outcomes suggesting that lower limits of DBP goals may also apply. We examined the association between mean attained DBP and cardiovascular (CV) outcomes in patients who achieved an on-treatment SBP in the range of 120 to <140 mmHg in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND) trials on patients with high CV risk. This SBP range was associated with the lowest CV risk.

Methods We analysed the outcome data from patients age 55 years or older with CV disease from the ONTARGET and TRANSCEND trials that randomized high-risk patients to ramipril, telmisartan, and the combination. In patients with controlled SBP (on-treatment 120 to <140 mmHg), the composite outcome of CV death, myocardial infarction, stroke and hospital admission for heart failure, the components thereof, and all-cause mortality were analysed according to mean on-treatment DBP as categorical (<70, 70 to <80, 80 to <90, and ≥90 mmHg) and continuous variable as well as the change of DBP according to baseline DBP. Pulse pressure (PP) was related to outcomes as a continuous variable.

Results In 16 099 of 31 546 patients, mean achieved SBP was 120 to <140 mmHg. The nominally lowest risk for all outcomes was observed at an achieved DBP of 70 to <80 mmHg. A higher achieved DBP was associated with a higher risk for the outcomes of stroke and of hospitalization for heart failure (≥80 mmHg) and myocardial infarction (≥90 mmHg). A lower achieved DBP (<70 mmHg) was associated with a higher risk for the primary outcome [hazard ratio (HR) 1.29, 95% confidence interval (95% CI) 1.15–1.45; P < 0.0001], myocardial infarction HR 1.54 (95% CI 1.26–1.88, P < 0.0001) and hospitalization for heart failure HR 1.81 (95% CI 1.47–2.24, P < 0.0001) and all-cause death (HR 1.19, 95% CI 1.04–1.35; P < 0.0001) while there was no signal for stroke and CV death compared to DBP 70 to <80 mmHg. A decrease of DBP was associated with lower risk when baseline DBP was >80 mmHg. The associations to outcomes were similar when patients were divided to SBP 120 to <130 mmHg or 130 to <140 mmHg for DBP or PP.

Conclusion Compared to a DBP of 70 to <80 mmHg, lower and higher DBP was associated with a higher risk in patients achieving a SBP of 120 to <140 mmHg. Associations of DBP and PP to risk were similar notably at controlled SBP. These data suggest at optimal achieved SBP, risk is still defined by low or high DBP. These findings support guidelines which take DBP at optimal SBP control into consideration.

Take home figure J-curve relationship between achieved mean on-treatment systolic blood pressure (SBP) and the primary outcomes (cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure) (above) is shown in the total ONTARGET/TRANSCEND population (see also reference¹¹). At an optimal achieved on-treatment systolic blood pressure range (120 to <140 mmHg), a J-shape curve for the achieved on-treatment diastolic blood pressure (DBP) was explored. The increased risk at low diastolic blood pressure (even at optimal on-treatment systolic blood pressure levels) might be due to reverse causation (comorbidities, frailty, and progression of cardiovascular disease), adverse effect of overdosing of antihypertensive drugs or organ hypoperfusion potentially leading to cardiac damage. Concomitant low diastolic blood pressure at optimal systolic blood pressure might be associated with cardiovascular outcomes and physicians should be aware of the signal of increased risk. Guidelines should take into consideration lower boundaries of achieved on-treatment systolic blood pressure, diastolic blood pressure, and diastolic blood pressure even at optimal systolic blood pressure.