PATHWAY-2: Optimal treatment of drug resistant hypertension

Resistant hypertension can be defined as blood pressure not controlled to target despite treatment with maximal recommended and tolerated doses of A + C + D. The current NICE/BHS guidelines advise that such patients can be managed using a further diuretic, an alpha-blocker, or a beta-blocker, or that specialist advice is sought.

Which of these 4th line drugs is most likely to be effective is unclear however. Three possibilities are:

  1. It doesn’t matter – on average all drug classes will be the same
  2. One class of drug will always be better – the same mechanism underpins all resistant hypertension
    • One commonly proposed mechanism is that patients with resistant hypertension invariably have salt retention; a diuretic would therefore be expected to be the most effective drug
  3. The best class of drug will vary between patients
    • The hypertension unit in Cambridge routinely check renin levels in these patients, and base treatment on the results:

      pathway 2 hypothesis

PATHWAY-2 has the following two objectives:

  1. to evaluate whether resistant hypertension is invariably due to excessive sodium retention, and if further diuretic will be the most effective treatment
  2. to evaluate if plasma renin will predict the most effective 4th line drug

pathway 2 protocol

The protocol for PATHWAY-2 is shown above. Patients will be recruited if they have BP above target despite treatment with ACE inhibitor (or angiotensin receptor blocker), calcium channel blocker and diuretic. Patients will cycle through 4 therapeutic options, in a randomised order: additional diuretic (spironolactone), beta-blocker (bisoprolol), alpha-blocker (doxazosin), or a placebo. Each drug will be given at a lower dose for 6 weeks, and then increased for a further 6 weeks. Blood pressure and biochemical measurements will be made at the start of the study, and at the end of each 12 week period.

British Heart Foundation British Hypertension Society