Do you foresee a paradigm shift in the treatment of hypertension in coming years?
Dr. Bakris: It’s already happening. If you look at the 2011 NICE [National Institute for Health and Clinical Excellence, in the United Kingdom] guidelines, European guideline updates, Australian guidelines, it’s clear that people have moved to using renin-angiotensin system blockade or calcium antagonists as initial therapy, quickly moving to combine them if appropriate, and, if appropriate, starting with combination therapy in people with blood pressure of 160 or higher. Diuretics are recommended as third-line agents in these guideline approaches.
There’s a paradigm shift as well to diuretics such as chlorthalidone and indapemide, and away from hydrochlorothiazide. This has already happened in the U.K. and the upcoming JNC 8 [8th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure]. Given the burgeoning increases in obesity and increased longevity, the initial role of combination therapy is alive and well, and gathered a lot of momentum in the U.S., but especially so outside the U.S.
Where should the pharmaceutical industry focus its efforts in the development in antihypertensive agents?
Dr. Bakris: Researchers have just identified 19 different candidate genes for hypertension and interestingly, a lot of them have interactions with natriuretic peptide genes and actually don’t present a prominent role of the renin-angiotensin system. I would wait until the genetics of hypertension are better understood, especially since at least nine of those genes affect natriuretic peptide synthesis.
We don’t need another blocker of the RAS, we don’t need another calcium antagonist, we don’t need another beta blocker. We have enough of those [medications] and what we have is pretty good. I think it’s important for them [pharmaceutical companies] to pause at this point and wait for the basic science to catch up to where they are.
They should explore better [drug] combinations. They’ve exhausted combinations with specific classes of drugs, but there are also meaningful combinations of other agents that may warrant some investigation.
Study findings presented at the recent 48th Congress of the European Renal Association-European Dialysis and Transplant Association showed a cardiovascular benefit to taking BP medications at bedtime rather than in the morning. Do you think physicians should advise patients to take their meds before turning in for the night?
Dr. Bakris: That is a double-edged sword. Most people with chronic kidney disease, specifically with GFR’s of 30 or less, tend to not dip at night. Nondipping is associated with higher cardiovascular risk, no question about that. So, does taking your meds at night necessarily transform you into a dipper? We used to think that, and there are studies showing that taking meds at night will transform hypertensive individuals with normal kidney function into dippers.
We did a study, which was not published, of a subset of patients in the African-American Study of Kidney Disease. Patients had CKD, with GFR’s of 35-40, and most had microalbuminuria. All were on ACE inhibitors and other agents.
In random fashion, some patients were dosed at night. We evaluated 24-hour ambulatory blood pressure monitoring (ABPM). Patients failed to convert and start dipping. And there are other studies showing that dosing at night does not necessarily cause patients to become dippers. It’s not just the timing of the blood pressure medication.
Dipping is affected by the quality of sleep, things you drink before you go to bed especially those with caffeine, and other factors. If you want to dose medications at night, I’m all for it, and I do it after I get the results of a 24-hour ABPM If they’re not dippers, then I feel very comfortable dosing them at night. On the other hand, if you dose at night, you run the risk of transforming people into hyper dippers. With such excessive dipping, they run the risk of become hypotensive while they’re sleeping. These patients have an even higher mortality rate than those who don’t dip.
Do you think the current thresholds that define hypertension (e.g., 120/80 mm Hg) for the general population and 130/80 mm Hg for diabetics) are appropriate?
Dr. Bakris: For the general population, 120/80 mm Hg is fine. For diabetics, the guidelines have changed. Already in the U.K. and Europe, the goal blood pressure based on evidence from clinical trials is 140/90 mm Hg. In diabetes, the only place that’s going to retain the goal of less than 130/80 mm Hg is Australia, and even there it’s with a qualification that patients can tolerate it. If they can’t, then the goal is 140/90 mm Hg.
With diabetics, 130/80 mm Hg makes sense. You should be more aggressive, but it doesn’t result in lower mortality. It does result in lower stroke rates, which is important. In the U.S. and Australia, they’re saying definitely less than 140/90 mm Hg and patients should be made aware that there could be an additional benefit with relation to stroke if they can achieve a pressure below 130/80 mm Hg.
For CKD, in the absence of proteinuria, you cannot defend a blood pressure of less than 130/80 mm Hg, you can only defend a blood pressure of less than 140/90 mm Hg in regard to slowing nephropathy progression. For everybody except those with advanced proteinuric kidney disease, the goal blood pressure is less than 140/90 mm Hg, and in certain subgroups like diabetics, you can certainly discuss the advantages potentially of going below 130/80 mm Hg.