Is RDN effective or ineffective in treating refractory hypertension?

Is RDN effective or ineffective in treating refractory hypertension?  At present, despite the existence of a variety of safe and effective antihypertensive drugs, the rate of achieving blood pressure control in hypertensive patients is still generally poor.

Some device interventional therapies have been introduced to treat hypertension. Among them, the most widely studied method is transcatheter renal sympathetic denervation (RDN), which aims to interrupt the afferent and efferent renal sympathetic nerve activity by applying radiofrequency energy, ultrasound energy or injecting alcohol into the perivascular space.

For patients with or without medications for hypertension, the second-generation placebo-controlled trial provides solid evidence for the efficacy of radiofrequency and ultrasound RDN in reducing blood pressure. In addition, in all registration studies and clinical trials, the safety of RDN seems to be very good. However, there are still several problems that need to be resolved.

Recently, Progress in Cardiovascular Diseases published a review that summarized the basic principles and current evidence of catheter-based RDN, and discussed some unresolved issues and possible future indications.

Early experience with RDN

The open-label randomized controlled study (RCT) SIMPLICITY HTN-1 and SIMPLICITY HTN-2 demonstrated the feasibility of using unipolar SYMPLICITY Flex radiofrequency catheter treatment for RND in patients with severe drug-resistant hypertension. The study showed that RDN can be significant Reduce the systolic blood pressure measured in the office, and the safety is better. Subsequent observational studies have also verified the conclusions of the SIMPLICITY HTN-1 and SIMPLICITY HTN-2 studies.

However, the early people’s enthusiasm for RDN research stopped abruptly after the results of the SYMPLICITY HTN-3 study were announced. As the first sham operation controlled study, the SYMPLICITY HTN-3 study included 535 patients with drug-resistant hypertension who were randomized to receive RDN and sham operation, and the superiority cutoff for the RDN group was set at 5 mmHg. Although the safety of RDN was confirmed, the SYMPLICITY HTN-3 study failed to prove that RDN was superior to the sham operation group in terms of lowering blood pressure. ±25.9 mmHg).

The DENERHTN study is a randomized controlled, end-point blinded evaluation study. It aims to evaluate the therapeutic effect of using SYMPLICITY Flex catheter for RDN on patients with refractory hypertension on the basis of standard drug therapy. The study used toxicological analysis at baseline and 6 months to assess patients’ compliance with antihypertensive medications.

The results of the study show that on the basis of drug therapy, the blood pressure reduction effect of RDN is significantly better than that of standard drug therapy alone. It is worth noting that at 6 months, only about 50% of patients in the two groups insisted on taking antihypertensive drugs, although all patients provided written informed consent for toxicological analysis and were told to comply with drug treatment Objectively evaluate the sex. A post-mortem analysis of the DENERHTN trial showed that non-adherence to treatment was the main determinant of the difference between office systolic blood pressure and day-to-day ambulatory blood pressure.

Second-generation RDN research

The results of the SYMPLICITY HTN-3 study have caused widespread controversy, and even experts in the field of hypertension treatment have begun to question the feasibility of RDN.

The post-event analysis of the SYMPLICITY HTN-3 trial and the in-depth interpretation in the recommendations provided by an international expert group defined the best trial design, methodology, and patient population to be included in the RDN trial for this type of research. The SPYRAL HTN global clinical trials of catheters (including the SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED studies) and the ultrasound catheter-based RADIANCE-HTN trial design provide useful information. In response to the deficiencies of previous studies, these two studies have made many meticulous improvements in research design.

These carefully designed and executed sham operation controlled phase II trials showed that in patients with mild to moderate hypertension, ultrasound and radiofrequency RDN treatment can reduce ambulatory blood pressure and office blood pressure, and the reduction in blood pressure has clinical significance, regardless of whether the patient is in Whether to continue to use antihypertensive drugs after RDN.

At present, there is also a third-generation catheter-Peregrine catheter that injects alcohol into the space around the renal arteries. Animal experiments and small-scale open-label studies have shown that it has a good antihypertensive effect and safety. Two sham operation controlled studies-TARGET BP I and TARGET BP OFF-MED are currently underway.

Problems to be solved:

Sham operation-controlled clinical studies provide reliable evidence for the efficacy and safety of radiofrequency and ultrasound RDN in reducing blood pressure in the short term. However, several questions remain unanswered.

1. Can RDN surgery be optimized?

Pre-clinical studies have shown that increasing the number of ablations is not sufficient to produce a clear dose-response relationship with renal norepinephrine tissue content. Moreover, the relationship between the selection of renal nerve segment ablation and the effect of lowering blood pressure is not clear.

Although the surgical procedure is optimized, the responsiveness of patients to RDN is still different, and some patients may lack sufficient blood pressure responsiveness due to incomplete ablation of sympathetic nerve fibers.

In preclinical research, histopathological analysis is the gold standard for verifying RDN. So far, there is no clinical method to immediately monitor the effect of renal nerve ablation. Currently, three monitoring methods have been studied: (1) direct nerve stimulation, (2) indirect testing induced by reflex (mental stress, head tilt, lower body negative pressure and isometric grasping, etc.), (3) passive monitoring (renal deprivation) Norepinephrine/renin overflow rate, blood pressure-flow monitoring).

2. Is the effect of RDN blood pressure lasting?

Although RDN can continue to lower blood pressure in the short term, there is still a lack of relevant data on the long-term efficacy.
So far, there is uncertainty about the possibility of renal reinnervation after RDN.
Preclinical studies have shown that anatomical rather than functional reinnervation may occur after RDN.

3. Can RDN reduce the risk of cardiovascular disease?

After the use of antihypertensive drugs, for every 10 mmHg reduction in systolic blood pressure in the office, the risk of major cardiovascular diseases can be significantly reduced by 20%, the risk of coronary heart disease is reduced by 17%, the risk of stroke is reduced by 27%, the risk of heart failure is reduced by 28%, and all-cause death The rate is reduced by 13%.

However, it is not clear whether these beneficial effects related to blood pressure can be equivalent to the benefits of device antihypertensive therapy. A meta-analysis showed that RDN has a beneficial effect on cardiovascular target organ damage in patients with refractory hypertension, but the follow-up time of most (76%) studies is limited to 6 months (the longest follow-up time is 12 months) ).

4. Which patients are the ideal target populations for RDN?

Early trials (including trials specifically for the treatment of patients with refractory hypertension) have provided convincing evidence for the safety of RDN. Recent studies have shown that RDN can be used in patients with mild to moderate hypertension (with/without antihypertensive drugs). The antihypertensive effect provides evidence.

Compared with antihypertensive drugs, RDN has two significant advantages: First, the lowering of blood pressure can continue throughout the day, and has nothing to do with blood drug concentration. Secondly, RDN blood pressure has nothing to do with whether or not to adhere to antihypertensive drugs. Therefore, RDN may provide an alternative treatment for patients who are intolerant or unwilling to take antihypertensive drugs.

In addition, RDN may be a treatment option for other diseases characterized by increased sympathetic nerve activity, such as chronic kidney disease, metabolic syndrome, heart failure, myocardial infarction, atrial fibrillation, and ventricular tachycardia. For patients with atrial fibrillation, RDN is not only expected to assist pulmonary vein isolation to reduce atrial fibrillation recurrence, but also as a means of primary prevention of atrial fibrillation in patients with high-risk hypertension/non-hypertension.

In cardiovascular interventions, RDN is the most frequently studied treatment method in sham operation controlled trials. Both radiofrequency and ultrasound RDN can continuously reduce the clinic and ambulatory blood pressure of hypertensive patients, regardless of whether they continue to take antihypertensive drugs.

Future research on RDN should focus on:

(1) Identify the patient groups with the highest response to RDN;

(2) Determine a reliable and simple method to verify the integrity of the ablation during the operation;

(3) To study the application of RDN in other patients with increased sympathetic nerve activity, including but not limited to heart failure and arrhythmia.

(source:internet, reference only)

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