SPYRAL PIVOTAL - SPYRAL HTN-OFF MED Study

All-cause mortality End-stage Renal Disease (ESRD) Significant embolic event resulting in end-organ damage Renal artery perforation requiring intervention Renal artery dissection requiring intervention Vascular complications Hospitalization for hypertensive crisis not related to confirmed non-adherence with medications or the protocol New renal artery stenosis >70% (6 months for new renal artery stenosis)

The outcome measure is the change in ambulatory systolic blood pressure from baseline to 3-month. The unadjusted treatment difference between renal denervation and sham control groups is -3.9 mmHg. The baseline adjusted treatment difference is -3.9 mmHg.

Significant embolic event resulting in end-organ damage (e.g. kidney/bowel infarct, lower extremity ulceration or gangrene, or doubling of serum creatinine documented by at least two measurements at least 21 days apart)

Renal artery perforation requiring intervention

Number of Participants with Renal artery dissection requiring intervention

Vascular complications (e.g., clinically significant groin hematoma, arteriovenous fistula, pseudoaneurysm, excessive bleeding) requiring surgical repair, interventional procedure, thrombin injection, or blood transfusion (requiring more than 2 units of packed red blood cells within any 24 hour period during the first 7 days post renal denervation procedure).

defined as two or more eGFR measurements < 15 mL/min/1.73m2 at least 21 days apart and requiring dialysis for one of more of the following:

• Volume management refractory to diuretics
• Hyperkalemia unmanageable by diet and diuretics
• Acidosis bicarbonate <18 unmanageable with HCO3 supplements
• Symptoms of uremia, nausea, vomiting

≥40% decline in eGFR

Number of Participants with New myocardial infarction

Number of Participants with New stroke

Renal artery re-intervention

Major bleeding according to TIMI definition (i.e. intracranial hemorrhage, ≥5g/dl decrease in hemoglobin concentration, a ≥15% absolute decrease in hematocrit, or death due to bleeding within 7 days of the procedure).

Increase in serum creatinine > 50% from screening visit 2.

Hospitalization for hypertensive crisis not related to confirmed non-adherence with medications or the protocol.

Change in office systolic blood pressure from baseline (Screening Visit 2) to 1-month

Change in office diastolic blood pressure from baseline (Screening Visit 2)

Incidence of achieving target office systolic blood pressure (SBP <140 mmHg)

The outcome measure is the change in office systolic blood pressure from baseline to 3-month. The unadjusted treatment difference between renal denervation and sham control groups is -7.0 mmHg. The baseline adjusted treatment difference is -6.9 mmHg.

All-cause mortality

≥40% Decline in eGFR

Defined as two or more eGFR measurements < 15 mL/min/1.73m2 at least 21 days apart and requiring dialysis for one of more of the following:

• Volume management refractory to diuretics
• Hyperkalemia unmanageable by diet and diuretics
• Acidosis bicarbonate <18 unmanageable with HCO3 supplements
• Symptoms of uremia, nausea, vomiting

New Myocardial Infarction

Number of Participants with New Stroke

Renal Artery Re-intervention

Major bleeding according to TIMI definition (i.e. intracranial hemorrhage, ≥5g/dl decrease in hemoglobin concentration, a ≥15% absolute decrease in hematocrit, or death due to bleeding within 7 days of the procedure).

Number of Participants with Increase in Serum Creatinine > 50% from screening visit 2.

Hospitalization for Hypertensive Crisis Not Related to Confirmed Nonadherence With Medications or the Protocol

Change in diastolic blood pressure from baseline (screening visit 2) to 3-month as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM).

Change in Office Diastolic Blood Pressure From Baseline (Screening Visit 2) to 3-months

Incidence of Achieving Target Office Systolic Blood Pressure (SBP <140 mmHg)

Confirmed by angiography and as determined by the angiographic core laboratory.

Change in diastolic blood pressure as measured by 24-hour ABPM

Change in Office Systiloc Blood Pressure From Baseline (Screening Visit 2) to 36 months.

Change in office diastolic blood pressure

Defined as two or more eGFR measurements < 15 mL/min/1.73m2 at least 21 days apart and requiring dialysis for one of more of the following:

• Volume management refractory to diuretics
• Hyperkalemia unmanageable by diet and diuretics
• Acidosis bicarbonate <18 unmanageable with HCO3 supplements
• Symptoms of uremia, nausea, vomiting

≥40% Decline in eGFR

New Myocardial Infarction

New Stroke

Renal Artery Re-intervention

Major bleeding according to TIMI definition (i.e. intracranial hemorrhage, ≥5g/dl decrease in hemoglobin concentration, a ≥15% absolute decrease in hematocrit, or death due to bleeding within 7 days of the procedure).

Number of Participants with Increase in Serum Creatinine > 50% from screening visit 2.

Confirmed by angiography and as determined by the angiographic core laboratory.

Hospitalization for hypertensive crisis not related to confirmed non-adherence with medications orthe protocol

Based on the prescribed medications reported, medication burden was calculated using Medication Index 2 score which is a composite index based on the doses of antihypertensive medications multiplied by the number of medications prescribed; all classes (ACE/ARB, calcium channel blockers, etc.) were considered equivalent in potency. Higher score indicates higher dosages being prescribed over the standard dose.

There are no clinically established thresholds.