Hypertension and The Kidney Update: Clinical Trials

1. Hypertension and The KidneyUpdate: Clinical Trials Paul J. Scheel, Jr., M.D. Director, Division of Nephrology The Johns Hopkins University School of Medicine

2. Primary Diagnosis in Patients With Kidney Disease Patient Primary Diagnosis Other Glomerulonephritis Diabetes 45% Hypertension USRDS 2010Annual Data Report. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government. Available at: www.usrds.org. Accessed 3/28/05.

3. Combination Therapy for BP Control: Rule Rather Than Exception Trial/Systolic Blood Pressure Achieved ALLHAT IDNT RENAAL UKPDS ABCD MDRD HOT AASK 138 mm Hg 138 mm Hg 141 mm Hg 144 mm Hg 132 mm Hg 132 mm Hg 138 mm Hg 128 mm Hg Number of BP Medications Adapted from Bakris et al. Am J Kidney Dis. 2000;36:646-661.

4. 95 98 101 104 107 110 113 116 119 Lower BP Slows Decline in GFR MAP (mmHg) 0 -2 -4 -6 Untreated HTN -8 GFR (mL/min/year) -10 -12 130/85 140/90 -14 Bakris GL et al. Am J Kidney Dis.2000; 36(3):646-661.

5. Hypertension and The KidneySignificant Publications 2013 • The Coral Trial • Symplicity HTN I, II, III Study • JNC VIII

6. Atherosclerotic Narrowing of Proximal Renal Artery

8. CORAL Trial • 947 Patients • Radomized • Medical Therapy • Medical Therapy plus Stent • Systolic HTN despite 2 or more drugs or CKD • Endpoints: Death,MI, Stroke, CHF, Progressive CKD or Need for Dialysis

9. Kaplan–Meier Curves for the Primary Outcome. Cooper CJ et al. N Engl J Med 2014;370:13-22.

10. Cooper et al.NEJM. 2014;370(1):13-22

11. The Coral TrialResults: • - No difference in composite end point between the treatment groups. • No difference in individual components of primary endpoint between the treatment groups. • Modest difference in control of systolic BP in patients treated with stents ( -2.3 mm Hg, P= 0.03)

12. Percutaneous Renal DenervationSymplicity HTN Study • Symplicity I, II, III HTN study designed to study efficacy of radiofrequency ablation of renal artery in patients with resistant HTN

14. Renal DenervationSymplicity

15. Renal Artery Denervation

16. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study • Open- Label Study of 153 patients with resistant HTN • Eligible Patients: BP > 160 mm Hg on 3 or more anti-hypertensives at “optimum dose” • End Point: Safety and Changes in BP over time. ww.thelancet.com Published online November 7, 2013

17. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study ww.thelancet.com Published online November 7, 2013

18. Renal Sympathetic Denervation for Treatment of Drug-Resistant Hypertension: One Year Results From the Symplicity HTN-2 Randomized Controlled Trial • RCT of Medical Therapy vs Renal Denervation with Cross Over • 106 Patients with > Drug Hypertension Randomized • Patients Randomized To Medical Therapy were Crossed Over to Renal Denervation at 6 months. • Patients Followed for 12 months • Primary Endpoint = Control of BP Esler et al. Circulation 2012; 18 (25): 2976-2982

19. Renal Sympathetic Denervation for Treatment of Drug-Resistant Hypertension: One Year Results From the Symplicity HTN-2 Randomized Controlled Trial Esler et al. Circulation 2012; 18 (25): 2976-2982

20. Symplicity 3 HTN Trial • 535 patients with resistant HTN in 87 US medical centers • Intervention: Radiofrequency ablation vs sham control. • Radomization: 2/3 intervention, 1/3 Sham • Endpoints: safety and efficacy at 6 months • Results: Not published. Press release. Study failed to meet efficacy endpoint at 6 months.

21. 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in AdultsReport From the Panel Members Appointed to the Eight Joint National Committee ( JNC 8) • Three Questions Answered: • 1) In adults with HTN, does initiating antihypertensive pharmacologic therapy at specific thresholds improve health outcomes ? • 2) In adults with HTN, does treatment with antihypertensive pharmacologic therapy to a specific BP goal lead to improvements in health outcomes ? • 3) In adults with HTN, do various antihypertensive drug or drug classes differ in comparative benefits and harms on specific health outcomes ? James et al. JAMA published online December 18, 2013

22. 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in AdultsReport From the Panel Members Appointed to the Eight Joint National Committee ( JNC 8) • Evidence Review: • 1) Mortality, CVD-related mortality,CKD-related mortality • 2) MI, CHF, hospitalization for CHF or CVA • 3) Need for coronary revascularizaton, PTA or stent placement (coronary, carotid,renal or lower extremities) • 4) ESRD, or doubling of serum creatinine or 50% reduction in measured GFR • 5) Included only RCT James et al. JAMA published online December 18, 2013

23. 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in Adults Report From the Panel Members Appointed to the Eight Joint National Committee ( JNC 8) James et al. JAMA published online December 18, 2013

24. Conclusions • PTA and endovascular stenting of the renal artery for atherosclerotic disease should not be routine practice • Renal artery denervation for resistant hypertension has shown initial promise and we will have to await publication of Simplicity 3 to determine its place in management of severe hypertension • JNC 8 has raised goal BP for most patients with HTN. Jury is still out for patients with CKD or CKD plus proteinuria