Over the years, a number of landmark clinical studies in the field of hypertension have been published, shaping how the disease is treated. Here are 5 that every pharmacist should know about:
1. DASH (1997)1
By the early 1990s it had been well-established that obesity, sodium intake, and alcohol consumption can influence blood pressure. Preliminary studies had shown positive results using both pharmacological and non-pharmacologic approaches to lowering blood pressure, including dietary and behavioral modifications. The DASH trial was a multicenter, randomized feeding study that tested the effects of dietary patterns on blood pressure. Unlike other studies published during the time, DASH tested the combined effects of nutrients that occur together in food rather than individual components.
The study enrolled 459 adults 22 or older, who were not taking antihypertensive medication and had a systolic blood pressure (SBP) of less than 160 mmHg and diastolic blood pressure (DBP) of 80 to 95 mmHg. During a three-week run-in phase, all subjects were fed a control diet that was low in fruits, vegetables, and dairy products, with a fat content typical of the average diet in the United States. They were then randomly assigned to receive 1 of 3 diets for eight weeks: the control diet; a diet rich in fruits and vegetables; or a “combination” diet rich in fruits, vegetables, and low-fat dairy products, with reduced saturated and total fat. The sodium intake was similar among each diet. The primary outcome was a change in DBP at rest. A change in SBP was a secondary outcome.
The study results showed that the combination diet resulted in the most significant reductions in blood pressure, compared with the other 2 groups. Specifically, the combination diet reduced SBP by 5.5 mmHg more and DBP by 3.0 mmHg more than the control diet (P<.001 for each). The SBP and DBP reductions with the fruits-and-vegetables diet were 2.8 mmHg (P<.001) and 1.1 mmHg greater than with the control diet (P=.07). When compared with the fruits-and-vegetables diet, the combination diet reduced SBP by 2.7 mmHg more (P=.001) and DBP by 1.9 mmHg more (P=.002). Results were similar after adjusting for changes in weight.
A follow-up study published in 2001 found that restricting sodium levels in combination with the DASH diet can substantially lower blood pressure. Today, the DASH diet is a commonly recommended diet for healthy weight loss and lowering blood pressure.
Conclusion: A diet rich in fruits, vegetables, and low-fat dairy foods, with reduced saturated and total fat can substantially lower blood pressure.
2. ALLHAT (2002)2
Antihypertensive drug therapy has been shown in numerous studies to substantially reduce the risk of hypertension-related morbidity and mortality. However, by the early 2000s, the optimal choice for initial pharmacotherapy of hypertension was uncertain. Specifically, little data were available about the effect of various classes of antihypertensives on the risk of coronary heart disease (CHD) and with the benefit in high-risk groups, such as older patients, African-Americans, and those with diabetes.
To answer these questions, researchers conducted a randomized, double-blind, multicenter trial to determine whether the occurrence of fatal CHD or nonfatal myocardial infarction (MI) is lower for high-risk patients with hypertension treated with amlodipine, lisinopril, doxazosin, or chlorthalidone. A total of 33,357 participants 55 and older with hypertension and at least 1 other CHD risk factor were enrolled in the study and followed up for a mean 4.9 years. During an interim analysis, the doxazosin arm was terminated early because of a significantly increased risk of CHF, compared with chlorthalidone, and therefore, its data were not included in the final analysis.
Upon analysis of the data, the primary outcome, fatal coronary artery disease or nonfatal MI at 6 years, was similar among all groups. There was also no significant difference in all-cause mortality, a secondary outcome, among the groups. Outcomes were found to be consistent when looking at age, gender, race, and diabetic subgroups. When comparing amlodipine with chlorthalidone, the amlodipine group had a 38% higher risk of heart failure (HF) (P<.001) and a 35% higher risk of hospitalized/fatal HF (P<.001). When comparing lisinopril with chlorthalidone, the lisinopril group had a 15% higher risk for stroke (P=.02), a 10% higher risk of combined cardiovascular disease (CVD) (p<0.001), a 19% higher risk of HF (P<.001), and an 11% higher risk of hospitalized/treated angina (P=.01).
As a result, the authors of the study concluded that thiazide-type diuretics are superior in preventing CVD and recommended that they be preferred for first-step antihypertensive therapy. Because of results from the study, the JNC 7 hypertension guidelines recommended that diuretics should be initiated in stage I hypertension.
Conclusion: In patients with hypertension, chlorthalidone, amlodipine, and lisinopril performed similarly with regard to fatal CAD and nonfatal MI. However, chlorthalidone was superior when looking at secondary cardiac outcomes.
3. HYVET (2008)3
Treatment benefits of blood pressure reduction had been widely established by 2008. However, there was inconclusive evidence on the benefit of treating patients 80 and older, as many hypertension trials had excluded this population. Some preliminary epidemiologic studies had suggested that there is an inverse relationship between blood pressure and the risk of death among people 80 and older, potentially reflecting an increased risk of therapy for blood pressure reduction in this population. Additionally, a 1999 meta-analysis looking at treating hypertension in this age group found evidence of a 36% reduction in the risk of stroke but a 14% increase in the risk of all-cause mortality.
As a result, researchers conducted the HYVET study to better understand the clinical benefits and risks of antihypertensive treatment in elderly patients. A total of 3845 patients 80 and older with a sustained SBP of 160 mmHg or more were randomly assigned to receive either the diuretic indapamide or matching placebo. The ACE inhibitor perindopril, or matching placebo, was added if necessary to achieve the target blood pressure of 150/80 mmHg. The primary endpoint was fatal or nonfatal stroke.
After a mean follow-up duration of 1.8 years, study results showed a 30% reduction in fatal or nonfatal strokes in the active treatment group versus placebo, though it did not reach statistical significance (95% CI 0.49-1.01; p=0.06). Significant reductions were seen in several secondary endpoints, including a 39% reduction in the rate of death from stroke (95% CI 0.38-0.99; p=0.046), a 21% reduction in the rate of death from any cause (95% CI 0.65-0.95, p=0.02), and a 64% reduction in the rate of HF (95% CI 0.18-1.28; P=0.14). Fewer serious adverse events were reported in the active-treatment group (358 versus 448; P=.001). Upon publication, HYVET became one of the few individual studies of hypertension showing benefits of blood pressure reduction on mortality. Results from this study and several others led to the JNC 8 recommendation that elderly patients 60 and older be treated to a blood pressure of <150/90.
Conclusion: Among elderly patients with hypertension, treatment with a diuretic with or without an ACE inhibitor appears to be beneficial, though some of the endpoints did not reach statistical significance.
4. ACCOMPLISH (2008)4
The JNC 7 treatment guidelines recommended that when combination antihypertensive therapy is warranted, thiazide diuretics should be considered. However, preliminary data suggested that the combination of benazepril, an ACE inhibitor, and amlodipine, a calcium-channel blocker, may offer an additional clinical benefit.
To further explore the effects of combination antihypertensive therapies, researchers conducted a randomized, double-blind trial with more than 11,000 patients with hypertension who were at high risk for cardiovascular events. Participants were randomly assigned to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary endpoint was the composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization.
The trial was ultimately terminated early after a mean follow-up of 36 months after the boundary of the prespecified stopping rule was exceeded. Analysis of the data showed that there were 552 primary-outcome events in the benazepril–amlodipine group (9.6%) and 679 in the benazepril–hydrochlorothiazide group (11.8%), representing a statistically significant 19.6% relative risk reduction favoring the benazepril-amlodipine group (95% CI 0.72-0.90; p<0.001). Additionally, there was a 22% reduction in the rate of fatal and nonfatal MI, favoring benazepril-amlodipine (95% CI 0.62-0.99; p=0.04). Death from any cause and fatal and nonfatal stroke favored benazepril-amlodipine. However, the results did not reach statistical significant (P=.08 and .17, respectively). The drop-out rate due to adverse events was similar among the 2 groups.
Conclusion: In patients with hypertension at high risk for cardiovascular complications, the combination of benazepril-amlodipine is superior to benazepril-hydrochlorothiazide in reducing cardiovascular events.
5. SPRINT (2015)5
Despite numerous studies showing that treating hypertension reduces the risk of CVD outcomes, there has been uncertainty regarding the target for SBP lowering. Observational studies have shown a progressive increase in cardiovascular risk as SBP rises above 115 mmHg, and treatment guidelines have recommended to treat hypertension to a target SBP of <140 mmHg, but no large well-conducted trials have examined the impact of more intensive lowering of blood pressure.
In 2015, researchers published the results of SPRINT, a randomized controlled, open-label trial conducted at 102 clinical sites in the United States. In the trial, 9361 participants with a SBP of 130 mmHg or higher, presenting with an increased cardiovascular risk, but without diabetes, were randomly assigned to a SBP target of less than 120 mmHg (intensive treatment) or less than 140 mmHg (standard treatment). After the participants underwent randomization, their baseline antihypertensive regimens were adjusted accordingly, based on study-group assignment. The primary composite outcome was MI, other acute coronary syndromes, stroke, HF, or death from cardiovascular causes.
The study was stopped early after a median follow-up of 3.26 years because of a statistically significant 25% reduction of the primary composite outcome in the intensive-treatment group, compared with the standard-treatment group (1.65% per year versus 2.19% per year; 95% CI 0.64-0.89; p<0.001). All-cause mortality, a secondary outcome, was also significantly lower in the intensive-treatment group (HR=0.73; 95% CI 0.60-0.90; p=0.003), with separation in mortality becoming apparent at about 2 years. Importantly, there were higher rates of serious events with the intensive-treatment group than the standard treatment group, including hypotension (2.4% versus 1.4%, P=0.001), syncope (2.3% versus 1.7%, p=.05), electrolyte abnormality (3.1% versus 2.3%, p=0.02), and acute kidney injury or failure (4.1% versus 2.5%, P<.001)
Conclusion: Among patients at high risk for cardiovascular events but without diabetes, intensive blood pressure control to a target SBP <120 mmHg improves cardiovascular outcomes but increases the rates of some adverse events.
1. Appel LJ, Moore TJ, Obarzanek E. et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med. 1997;336(16):1117-24.
2. ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA. 2002;288(23):2981-2997. doi:10.1001/jama.288.23.2981.
3. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008. 358(18):1887-1898.
4. 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. doi: 10.1056/NEJMoa0801369.
5. The SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-16. doi: 10.1056/NEJMoa1511939.
Timothy O'Shea, MS, PharmD
Timothy O'Shea, MS, PharmD, is a Clinical Pharmacist working at a regional health insurance plan on the east coast. Additionally he works per diem at a nationwide retail pharmacy chain. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency. He completed his M.S. in Health Services Administration, with a focus on Health Economics and Outcomes, in 2018. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.