ATLANTA — Stubbornly refractory hypertension can be approached with a number of drug combinations and other novel treatments, Dr. Angela L. Brown said at a meeting sponsored by the International Society on Hypertension in Blacks.
The combination of a diuretic and an inhibitor of the renin-angiotensin-aldosterone system (RAAS) is probably the most popular choice, said Dr. Brown of Washington University, St. Louis. This combination makes physiological sense because the two classes of drugs have complementary modes of action. As the diuretic decreases fluid volume, the RAAS inhibitor decreases pulmonary vascular resistance.
Furthermore, RAAS inhibitors counteract the relative increase in blood pressure resulting from diuretic-induced renin secretion. The combination is well tolerated, and it's effective in low-renin populations and African Americans.
Another popular combination is an ACE inhibitor along with a calcium channel blocker (CCB). The ACE inhibitor blocks the renin-angiotensin system, is effective in high-renin hypertension, works in all populations—especially whites, Hispanics, and young patients—and produces arterial and venous vasodilation. The CCB blocks the sympathetic nervous system, provides excellent efficacy, produces arterial vasodilation, is effective in low-renin hypertension, and works in all populations—particularly African Americans and the elderly.
Theoretically, an ACE inhibitor along with an angiotensin II receptor blocker (ARB) should also work, since they would provide intervention at two points in the RAAS cascade, and the use of an ARB may block angiotensin II formed through the non-ACE-dependent pathway. But in reality, studies have not shown enhanced blood pressure reduction, although the combination does significantly reduce proteinuria levels.
The combination of a dihydropyridine CCB (such as amlodipine, nifedipine, or isradipine) along with a nondihydropyridine CCB (such as verapamil or diltiazem) may actually be more effective. The dihydropyridines are less likely to decrease cardiac output and may cause an acute reflux tachycardia. The nondihydropyridines decrease the pulse rate and may have a negative inotropic effect. The nondihydropyridines also inhibit the cytochrome P450 system and slow metabolism of the dihydropyridine CCBs. There's good evidence that this combination does decrease blood pressure, Dr. Brown said.
Two other novel treatments for refractory hypertension—insulin sensitizers or statins—take common comorbidities into account. “Most of the patients I see don't just come in with hypertension,” Dr. Brown said. “Maybe it's the blood pressure that gets them in the door, but when you get there and inspect them, they have dyslipidemia, they're obese, they have insulin resistance, [or] they have other cardiovascular risk factors that we have to treat.”
Thiazolidinedione insulin sensitizers bind to peroxisome proliferator-activated receptor gamma (PPARγ) in muscle and fat to decrease insulin resistance. Studies have shown that such receptors are also plentiful in the kidney and that two mutations in the PPARγ gene are associated with severe hypertension in humans. Pioglitazone appears to result in significant decreases in systolic blood pressure in clinical trials.
The statins reduce cholesterol, are atheroprotective and stabilize atherosclerotic plaques, have antioxidative effects, reduce inflammation and thrombus formation, and improve endothelial function. A small study has now shown that statins can reduce the magnitude of angiotensin-induced increases in blood pressure.
Nitrates are known to be effective for the acute treatment of severe hypertension and aortic dissection, but long-term use is hampered by tachyphylaxis and tolerance. Some studies have suggested, however, that intermittent dosing of long-acting nitrates resulted in a decrease in the augmentation index of the reflected pulse wave, thereby decreasing systolic blood pressure.
In addition to pharmacotherapy, there's at least one medical device that shows promise in treating refractory hypertension. The CVRx Rheos Baroreflex Hypertension Therapy System is an investigational implantable device that stimulates baroreceptors in the arterial walls of the carotid sinus. This simulates a rise in blood pressure that the brain works to counteract.
Studies have shown that the device causes a decrease in heart rate, a relaxation of blood vessels, and fluid release from the kidneys. Blood pressure in one patient was reduced from 186/98 mm Hg to 153/80 mm Hg in seconds by the use of the device. Dr. Brown, who disclosed that she has no ties to the manufacturer, said the device is well tolerated and causes no discomfort in patients.
She did disclose that she has received research support from GlaxoSmithKline and Novartis, is a consultant for Pfizer, and serves on speakers' bureaus for five pharmaceutical companies. The meeting was cosponsored by the American Society of Hypertension.