True Resistant Hypertension or True Noncompliance? A Push for Answers

Shelley Wood

June 15, 2014

ATHENS, GREECE — Doctors gathering here for HYPERTENSION 2014 , the joint European Society of Hypertension and International Society of Hypertension meeting, are turning with renewed attention to the question: just how many patients truly have "resistant" hypertension? Even more pressing, they say, is establishing once and for all what is the best way to get blood pressure down in these patients.

Those questions are on everyone's minds following the disappointing results of the SYMPLICITY 3 trial of renal denervation, where the newer interventional therapy was no better than medical care in patients deemed to have resistant hypertension at the study outset.

But as many commentators have noted, SYMPLICITY 3 patients randomized to the sham procedure ended up getting very intensive care, meaning that they were more likely to have their drugs changed or dosages increased, and accordingly, their blood pressures came down further than anticipated.

Here at HYPERTENSION 2014, a host of presentations focused on how to improve compliance in patients who aren't taking their meds and what might happen if they did.

In Norway, Dr F Fadl Elmula (Oslo University Hospital) and colleagues investigated blood-pressure lowering among "true resistant hypertension patients" referred for specialist care[1]. At the study outset, all patients were asked to bring their blood-pressure medications with them to their appointment and to take them in front of a study investigator, who then continued to monitor them further "to prohibit [them] throwing up the pills," Elmula said. Resistant hypertension was then reconfirmed via 24-hour ambulatory blood-pressure monitoring (ABPM).

This rigorous approach meant that of 65 resistant-hypertension patients referred for specialist care, a full 45 were excluded from the study: 14 for having found to be noncompliant with their meds, six for having white-coat hypertension, and 10 for having normalized BP after medication adjustment or treatment for primary hyperaldosteronism. At this point, 10 patients were randomized to renal denervation (one was found postrandomization to have Conn's disease and excluded) and 10 for adjustment/intensification of therapy.

After six and 12 months, Elmula showed, both office blood pressure and ABPM were significantly lower among patients who were managed by having their drug regimen intensified or changed as compared with those who underwent renal denervation. Those differences emerged as early as three months postrandomization, leading investigators to suspend further enrollment in the study, he added.

Looking at individual patients, only two of nine patients treated with renal denervation had daytime systolic blood pressures in the range of 135 m Hg or lower at six months, compared with seven of 10 in the medical group.

In an interview with heartwire , Elmula stressed the fact that more than two-thirds of specialist referrals for resistant hypertension were patients who were not taking their medications. And he rejected suggestions that renal denervation may not have been performed properly in this study, noting that the number of ablations were, on average, 7.9 for the left renal artery and 8.2 for the right renal artery, for a per-patient total of 16 successful ablations, "more than the average in many previous studies," he said.

Testing for Noncompliance

This question of true resistance (and true noncompliance) is driving investigators around the globe to find new and better ways of measuring noncompliance.

In the UK, Dr Christobelle White and colleagues (University of Leicester) have turned to spot urine analysis using mass spectrometry, essentially the same pathology lab tests used for toxicology screening, she said[2]. This is simple and reproducible and costs just £40 per analysis; it is able to detect as many as 40 drugs or drug metabolites within just 12 minutes per sample.

White presented the results of their urine testing in 208 consecutive patients, of whom 17 were patients referred for renal denervation.

Out of a mean of three drugs screened, the mean number of drugs detected was just 2.3, she said. A full 10% of patients screened had no drug/drug metabolites detectable in their urine samples, a number that rose to almost one in four among the patients referred for renal denervation.

"This is the most shocking figure," White said. "These were patients who were referred for an invasive, irreversible procedure, and yet they preferred to have that than take a pill."

When blood pressures for adherent and nonadherent patients according to urine samples were compared, not surprisingly, clinic systolic and clinic diastolic as well as daytime ambulatory diastolic blood pressures were all significantly higher, by approximately 10 mm Hg for each measurement, in the nonadherent patients.

Also of note, nonadherence tended to rise with the number of pills prescribed, such that more than half of patients prescribed five pills or more were found to be nonadherent.

The Most Pressing Problem

Other presentations tackled the question of measuring nonadherence using different methods. Polish researchers conducted a study that measured serum antihypertensive drug levels using liquid chromatography-tandem mass spectrometry, showing that just over 13% of patients prescribed at least four antihypertensive drugs appeared to be fully compliant. The same percentage were found to be taking none of their meds. The majority—86%—were found to be nonadherent to at least one of their medications.

Elsewhere, Dr Giuseppe Mancia (University of Milano-Bicocca, Milan, Italy) presented Italian data tackling patient noncompliance at a population level, looking at the number of patients who actually refilled drug prescriptions within 90 days. Mancia and colleagues have been tracking these data in the Lombardy region of Italy for many years, publishing several papers addressing this topic. Consistently, the number of patients who discontinue their drugs (according to pharmacy nonrenewals) hovers at around two-thirds, he showed.

"I think we can all agree, adherence to treatment may have a far greater impact on the health of the population than any improvement in specific medical treatments," Mancia said.

As for Elmula, he stressed to heartwire that "true" resistant hypertension is likely a much smaller proportion of patients than people have believed, and a lack of understanding of drug adherence is, in part, what drove the excitement for renal denervation. He believes that excitement has "been premature . . . since we still don't know that renal denervation really works and, number two, which type of patients benefit."

Some experts that argued that renal denervation may be a viable treatment not only for patients who have high blood pressure despite optimal treatment but also for patients who can't or won't take their drugs.

That may be true, said Elmula, but it still needs to be studied, and "that's a different study" from SYMPLICITY 3. Moreover, he points out, a patient who doesn't adhere to prescribed medications won't necessarily respond to renal denervation. Investigators have yet to pin down what predictors will identify "superresponders" to renal denervation, like the two out of nine patients in his study, and they need better ways of confirming when the therapy has been successful in the adequately denervated renal nerve.

Presenters disclosed having no conflicts of interest.

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