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? Kannel Lancet 2006: “The potential reasons for this increased hazard at lower levels of diastolic blood pressure include: a lower diastolic pressure might indicate increased pulse pressure; it might be a marker of frailty; or it might indicate reduction in coronary perfusion.” 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) Kannel Lancet 2006: “The potential reasons for this increased hazard at lower levels of diastolic blood pressure include: a lower diastolic pressure might indicate increased pulse pressure; it might be a marker of frailty; or it might indicate reduction in coronary perfusion.”

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

Does increased arterial stiffness explain the J-curve? 2207 hypertensive subjects Incidence of MI (/1000 person-years) 7798 subjects free of CVD (Framingham) Incidence rate of CVD 791 individuals with ISH (Framingham) Rate of recurrent CVD Madhavan et al. Hypertension 1994; 23:395-401 Kannel et al. Am J Cardiol 2004; 94:380-384 Frankin et al. Hypertension 2015; 65:299-305 The J-curve of diastolic BP is restricted to those with concomitant elevated PP/SBP Madhavan “it was only among patients with a wide PP that the curvilinear relation of diastolic BP fall to MI was found. Thus, pretreatment PP not only provides valuable prognostic information in itself but also is a useful tool in the identification of those patients in whom too large a treatment-induced fall in diastolic BP is likely to be associated with an increased risk of MI.” Kannel am j cardiol 2004 (stated by Kannel lancet 2006): « cardiovascular risk was increased in persons with a low diastolic blood pressure only if accompanied by an elevated systolic blood pressure, implicating pulse pressure.” « it appears that the excess CVD risk at low diastolic BP is largely confined to patients who also have an elevated systolic BP, implying that it is elevated pulse pressure (or isolated systolic hypertension) that is responsible for the excess risk observed at low diastolic BP.” Franklin hypertension 2015 « consistent with the hypothesis that increased CVD risk was associated with DBP <70 mm Hg only when combined with a pulse pressure of >=68 mmHg” …” CVD event rates were highest in the group with widened pulse pressure and DBP <70 mm Hg ompared with those with both low pulse pressure and low DBP, whether treated or untreated, supporting wide pulse pressure as an important risk modifier of the adverse effect from low DBP.” Blacher 2000 « The J-shaped relation to CVD risk that is associated with DBP presumably reflects, in large measure, increased arterial stiffness as manifested by a low DBP (and,by definition, a high PP)” Messerli 2009: « low DBP could be caused by an increased pulse pressure reflecting advanced vascular disease and stiffened large arteries”

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?

22,672 CAD patients treated for hypertension from the CLARIFY registry 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 pulse pressure and primary outcome Increased risk for high PP (≥ 65mmHg) … and for low PP (< 45 mmHg)

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

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

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

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 Pulse pressure is 55, 54, and 53 mmHg respectively in the <70, 70-79 and >=80mmHg subgroups (intermediate PP, circled part). Therefore, increased PP is not responsible for the increased risk observed at low DBP, which is, in addition is the exact same range for the whole population and for the lowest-risk PP subgroup

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 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 Even though elevated PP is associated with increased cardiovascular risk and is closely intertwined with decreased diastolic pressure, it does not appear to be the major determinant of the increased risk associated with low diastolic BP in this large cohort of CAD patients. A compromised myocardial perfusion associated with low diastolic BP in patients with CAD appears to be a more plausible explanation, although reverse causation cannot be ruled out.

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!

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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 HR of primary outcome 0.75 (95% CI 0.64 – 0.89) unattended BP 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