An analysis of 22,672 patients from the CLARIFY registry How can we explain the J-curve in hypertensive patients with coronary artery disease? An analysis of 22,672 patients from the CLARIFY registry Emmanuelle Vidal-Petiot*, Nicola Greenlaw, Ian Ford, Roberto Ferrari, Kim M Fox, Jean-Claude Tardif, Michal Tendera, Alexander Parkhomenko, Deepak L Bhatt, and Philippe Gabriel Steg, for the CLARIFY Investigators *DHU-FIRE, Hôpital Bichat, Assistance Publique - Hôpitaux de Paris Université Paris-Diderot, Inserm U1149 Paris, France

Emmanuelle Vidal-Petiot, MD-PhD Disclosures Non financial support from Servier The CLARIFY registry is supported by Servier. The sponsor had no role in the study design or in data analysis, and interpretation, but assisted with the set-up, data collection and management of the study in each country.

How can we explain the J-curve between BP and CV events? Vidal-Petiot et al. Lancet 2016; 388:2142-52

How can we explain the J-curve between BP and CV events? CLARIFY (Vidal-Petiot et al, Lancet 2016) HR of CV events Diastolic blood pressure ? ? ? Low myocardial perfusion Reverse causality Arterial stiffness (↑PP, ↓DBP)

Does increased pulse pressure explain the J-curve? Elastic arteries Stiff arteries no causal link ↑ PP ↓ DBP

Objective of the study Is the increased cardiovascular risk associated with low diastolic BP in hypertensive patients with CAD the result of elevated pulse pressure ̶ associated with low diastolic BP in patients with stiffened large arteries?

Study population 22,672 CAD patients treated for hypertension from the CLARIFY registry prospective longitudinal registry of 32,703 outpatients with stable CAD receiving standard care. Enrolled in 45 countries Age 65±10 years Male 75% Diabetes 33%

Outcomes and statistical analyses Primary outcome: Composite of cardiovascular death, myocardial infarction Relationships between BP categories and outcome: Cox proportional hazards model (unadjusted and adjusted) Covariates: Model 1: age, sex, geographic region, smoking status, MI, percutaneous coronary intervention, coronary artery bypass grafting, diabetes, LDL- and HDL-cholesterol, BMI, GFR, peripheral artery disease, hospitalization for or symptoms of heart failure, LVEF, ethnicity, stroke, transient ischaemic attack, and baseline medications (aspirin, statins, ACE inhibitors, ARB, beta-blockers, CCB, diuretics, and other antihypertensive medications) Model 2: ± mean arterial pressure (PP analysis), ± PP (diastolic BP analysis)

Relationship between diastolic BP and primary outcome J-curve relationship which persists after adjustment for multiple covariates …and after additional adjustment for pulse pressure

Relationship between pulse pressure and primary outcome 18% 16% 14% 12% 10% 8% 6% 4% Increased risk for high PP (≥ 65mmHg) Incidence rate (%) … and for low PP (< 45 mmHg) <45 mmHg 45-54 mmHg 55-64 mmHg 65-74 mmHg ≥75 mmHg

Cross-classification of diastolic BP and pulse pressure DBP<70 mmHg DBP 70-79 mmHg (ref) DBP≥80 mmHg Cross-classifications in 9 subgroups Pulse pressure PP<45 mmHg PP 45-64 mmHg (ref) PP≥65 mmHg

Cross-classification of diastolic BP and pulse pressure Total population The J-curve persists in the lowest -risk PP range

Cross-classification of diastolic BP and pulse pressure Total population The J-curve persists in the lowest -risk PP range

Cross-classification of diastolic BP and pulse pressure Total population The J-curve persists in the lowest -risk PP range P-value for interaction 0.005

Diastolic BP and pulse pressure: subgroup analysis The J-curve is attenuated as PP increases. A deleterious effect of a lower DBP may be compensated by the beneficial effect of a lower SBP.

Cross-classification of diastolic BP and systolic BP DBP<70 mmHg DBP 70-79 mmHg (ref) DBP≥80 mmHg Cross-classifications in 9 subgroups Systolic BP SBP<120 mmHg SBP 120-139 mmHg (ref) SBP≥140 mmHg Vidal-Petiot et al. Lancet 2016; 388:2142-52

Cross-classification of diastolic BP and systolic BP Total population The J-curve persists in the lowest -risk SBP range P-value for interaction 0.24

Conclusion Elevated pulse pressure is independently associated with increased cardiovascular risk However, elevated pulse pressure is not the major determinant of the increased risk associated with low diastolic BP in this large cohort of CAD patients

Discussion and Perspectives Observational studies: association in not causation Methods to attenuate influence of reverse causality 1/excluding frail patients 2/adjusting for confounders 3/sensitivity analyses (age, heart failure…) 4/time-updated analyses 5/pathophysiological plausibility for causation … Satter Circulation 2017; 135:2369-72 Observational studies help generate hypotheses. Only future RCTs will provide definite proof on potential harmfulness of excessive pharmacological lowering of diastolic BP.

Thank you for your attention!

(additional slides)

Baseline characteristics of the patients

Optimal BP targets: the J-curve controversy SPRINT CLARIFY risk of cardiovascular events systolic blood pressure HR of primary outcome 0.75 (95% CI 0.64 – 0.89) diastolic blood pressure Wright et al. NEJM 2015; 373:2103-16 Vidal-Petiot et al. Lancet 2016; 388:2142-52

Optimal BP targets: the J-curve controversy 151 mmHg risk of cardiovascular events systolic blood pressure 136 mmHg unattended BP HR of primary outcome 0.75 (95% CI 0.64 – 0.89) diastolic blood pressure Wright et al. NEJM 2015; 373:2103-16 Vidal-Petiot et al. Lancet 2016; 388:2142-52

Does low myocardial perfusion explain the J-curve? Rabkin et al. Am J Hypertens 2016; 29:1085-93