Treating Hypertension Part III: Pharmacologic Management

Hypertension, commonly referred to as a “silent killer,” remains a major figure in the long list of clinical issues facing patients and clinicians. MD Magazine: Peers & Perspectives recently convened an expert discussion on managing hypertension featuring three of the nation’s leading hypertension specialists: Jan Basile, MD, professor of medicine in the division of general internal medicine/geriatrics at the Medical University of South Carolina; Keith C. Ferdinand, MD, adjunct clinical professor at the Morehouse School of Medicine; and Karol E. Watson, MD, associate professor of medicine in the division of cardiology at UCLA. The panel was moderated by Peter Salgo, MD, professor of anesthesiology and internal medicine at Columbia University. (This is the last part of a three-part article. To read the first part, click here. To read the second part, click here.)


Pharmacologic Management of Hypertension

Salgo asked what sort of changes JNC 8 might make in recommendations for drug therapy. “Do you have any thoughts about changing paradigms?” he asked. “Is  there going to be a preference for use of specific agents within classes?”

“There is increasing data that the lowdose approach to thiazide diuretics may be safer and better tolerated in some patients, but it may not have the same impact in terms of cardiovascular events,” replied Ferdinand. “It appears that adequate doses of thiazide diuretics is going to be something that the committee is going to have to embrace, versus just saying, ‘Put the person on the thiazide, and if they’re on the thiazide, there’s some inherent benefit.’”

By way of background, Ferdinand explained that in the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack) trial, a 25-mg dose of the thiazide diuretic chlorthalidone was found to be superior to amlodipine, a calcium channel blocker (CCB), and lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, in  terms of overall cardiovascular protection and far superior to lisinopril for stroke prevention among African Americans. (ALLHAT enrolled 42,418 patients age 55 or older with hypertension and at least one other risk factor for heart disease between 1994 and 1998 and continued into 2002. It was designed to determine whether occurrence of coronary heart disease was lower for high-risk hypertensive patients treated with newer anti-hypertensive drugs compared with a diuretic.¹)

In addition, Ferdinand pointed out that the ACCOMPLISH (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension) trial, which found a significant benefit in terms of reducing cardiovascular events from using a combination of benazepril, an ACE inhibitor, and amlodipine over a  combination of benazepril and hydrochlorothiazide, a thiazide diuretic, used a lower dose of hydrochlorothiazide than perhaps the equivalent dose of thiazide diuretics  used in other trials.

(ACCOMPLISH enrolled 11,506 patients with hypertension at high risk of cardiovascular events, and its primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization. After an  average of 30 months of treatment, primary-outcome events occurred in 9.6% of patients in the benazepril–amlodipine group compared with 11.8% in the benazepril–hydrochlorothiazide group.²)

Basile pointed out that when JNC 7 was released, both amlodipine and lisinopril were trade-name products and far more expensive than chlorthalidone, which was already generic, so it made sense to favor the thiazide diuretic given that it had been shown to be at least as effective as the others in the ALLHAT trial. Now that a number of other anti-hypertensive drugs are generic as well, he said, “I would personally like to see JNC 8 level the playing field, suggest chlorthalidone as the thiazide du jour, but also say that a clinician can use either an ACE and perhaps an ARB [angiotensin II receptor blocker], now that they are generic and will be at $4 a month, as a well as a CCB like amlodipine. I think that this will resonate more with the physician community than continuing to suggest that we know that a particular class of anti-hypertensive is best as initial therapy.”

Prognosis for Combination Therapy

“What’s the current guidance in terms of combination therapy?” asked Salgo. “Are we headed to some products which are going to be one pill with multiple drugs?”

“I do think in the future, practices will be accepting of more two-agent initial therapy, and I’m hoping that JNC 8 will emphasize the importance of this whole principle,” said Basile, noting that failing to reduce blood pressure within three to six months has been shown to have lasting consequences that are not overcome by reducing it later,  and that using two medications from the start helps get blood pressure under control sooner rather than later. For instance, he pointed out, the ACCOMPLISH trial found  that a combination of two medications—whether an ACE inhibitor and a diuretic or an ACE inhibitor and a CCB—was able to double the rate of blood pressure control  over six months from 37% to 74%.

“It’s going to be combination therapy and starting with combination therapy,” agreed Ferdinand, particularly for patients who are middle aged or older, African American, diabetic, or who have renal disease. “Those patients are going to need two drugs.” Salgo then asked whether many doctors were using direct renin inhibitors like  aliskiren, which has been available since 2007.

It is used, said Ferdinand, but it lacks the wealth of outcome studies that have been done on medications that have been available longer. “It may be used more frequently in the future, but we anxiously await those outcome studies before we leapfrog it over the agents that have been previously discussed,” he said.

“What about dual RAS [renin-angiotensin system] inhibition?” Salgo asked. “Any thoughts on that?”

Ferdinand pointed out that when an ACE inhibitor (ramipril) and an ARB (telmisartan) were taken together in the ONTARGET (Ongoing Telmisartan Alone and in  combination with Ramipril Global Endpoint) trial, the combination offered no benefit and led to an increase in side effects. (ONTARGET enrolled 25,620 patients with  coronary, peripheral, or cerebrovascular disease or diabetes with endorgan damage. Participants were given either ramipril, telmisartan, or a combination of the two. Over an average of 56 months, those in the combination-therapy group reached an average systolic blood pressure of 2 to 3 mm Hg lower than those receiving just ramipril, but they enjoyed no significant benefit in terms of primary outcome of death from cardiovascular causes, myocardial infarction, stroke, and hospitalization for heart failure. Those receiving combination therapy also had a significantly increased risk of hypotension, syncope, renal dysfunction, and hyperkalemia, with a trend toward increased  risk of renal dysfunction requiring dialysis.³)

Different Drugs for Different Patients?

“I have heard that RAS inhibition is preferable in the African-American population,” said Salgo. “Does that have any validity in the research?”

Since RAS inhibitors as monotherapy are not as effective at lowering blood pressure as thiazide diuretics and long-acting CCBs, Ferdinand said that there is no evidence that they are more effective for African Americans. However, he added that RAS inhibitors are beneficial to patients with renal disease, and since renal disease is more  common among African Americans, a greater percentage of them are likely to benefit from a RAS inhibitor. “But as a conventional first-step agent, I don’t think you can  make that argument because they may be less effective at lowering blood pressure in blacks,” he said.

“As a clinician, I am sensitive to one’s skin color, but our patients are more heterogeneous than ever before,” said Basile. “Rather than base a particular anti-hypertensive treatment on one’s skin color, we should base it on one’s risk. I think that we need to get away from looking at some of these demographic categorizations that appear to  be so absolute and, in reality, become arbitrary, and be more sensitive to the issues that will more effectively allow us to control blood pressure and improve outcomes in minority populations.”

“Is there any evidence that some drugs work better in women than in men or that the combination you would start for a woman would be different than in a man?” Salgo  asked.

“Reiterating what Jan just said, I think patients are all individual and there really is no good evidence that we should be treating women differently than men,” said Watson.
“A patient’s overall risk profile is what will guide your therapy more than what their skin color is or what their gender is.”

To close out the discussion, Salgo asked the panelists for their opinion on upcoming trends in hypertension treatment and a take-home message for primary care physicians who treat hypertension.

“I’d like clinicians to be compensated for the energy and effort that it takes to truly control blood pressure in their patient population,” said Basile, adding that in the  meantime he hopes clinicians will continue to do everything they can to help their patients reduce their blood pressure.

Ferdinand reminded clinicians to emphasize the  importance of lifestyle modification, a low-salt diet, and medication in combating hypertension. “We need to teach our  patients that medicines are not bad and, if used effectively, can lower heart attacks, strokes, and heart failure and improve survival,” he said.

Watson underscored the importance of treating patients as individuals. “There’s no one size fits all,” she said. “Everybody has different circumstances, different finances,  different medication tolerances. It’s very tough, and my hat is off to primary care physicians for doing such a great job with hypertension.”

“I’d like clinicians to be compensated for the energy and effort that it takes to truly control blood pressure in their patient population,” said Basile, adding that in the  meantime he hopes clinicians will continue to do everything they can to help their patients reduce their blood pressure.

Ferdinand reminded clinicians to emphasize the  importance of lifestyle modification, a low-salt diet, and medication in combating hypertension. “We need to teach our  patients that medicines are not bad and, if used effectively, can lower heart attacks, strokes, and heart failure and improve survival,” he said.

Watson underscored the importance of treating patients as individuals. “There’s no one size fits all,” she said. “Everybody has different circumstances, different finances,  different medication tolerances. It’s very tough, and my hat is off to primary care physicians for doing such a great job with hypertension.”


References
1. The ALLHAT Officers, et al. Major outcomes in high-risk hypertensive patients randomized to angiotensin converting enzyme inhibitor or calcium channel blocker vs. diuretic. JAMA. 2002;288(23):2981-2997.
2. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-2428.
3. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358(15):1547-1559.

To read the first part of this expert discussion, "Hypertension, the Silent Killer," click here. To read the second part, "Lifestyle Modification and Treatment Guidelines," click here.