Continuing Education

NEW DIRECTIONS IN THE MANAGEMENT OF HYPERTENSION
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This program (# 032-000-04-068-H01) is approved for 2 hours (0.2 CEU)
of continuing pharmaceutical education credit. A score of 70% on the examination is required to receive CE credit.

This lesson is no longer valid for CE credit after 12/31/2006

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New Directions in the Management of Hypertension
by
James T. Samuel, PharmD,
Rite Aid Pharmacy
Jackson, MS

Amanda James Wilburn, PharmD
James Bennett Apothecary
Corinth, MS

Deborah S. King, PharmD
University of Mississippi Medical Center
Department of Medicine
Jackson, MS

T. Kristopher Harrell, PharmD
University of Mississippi Medical Center
Department of Pharmacy Practice
Jackson, MS

Trenika Mitchell, PharmD
University of Kentucky
Chandler Medical Center
Lexington, KY

Needs Statement: In spite of intensive efforts, hypertension remains a major health concern in the U.S. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) continues to study and revise treatment guidelines, resulting in changes in the way hypertension is treated. Pharmacists must stay current with therapy if they are to be able to provide optimal care for their patients with high blood pressure.

Intended Audience: Pharmacists

Goal: To increase the awareness and understanding of recent updates in hypertension guidelines among pharmacy practitioners.

Objectives: Upon completion of this lesson, the pharmacist should be able to:
1. Summarize findings from recent clinical trials in the management of hypertension.
2. Identify changes in blood pressure classification and categories according to JNC-7 Guidelines.
3. Discuss the influence of lifestyle modifications on hypertension prevention and treatment.
4. Identify indications for specific drug classes in hypertension management.

Method of Participation: To obtain the associated two contact hours (0.2CEU) credit, participants must read the lesson, complete and submit the post-test along with the processing fee of $6.00. A minimum score of 70% is required in order to obtain credit. Statements of credit will be issued within 4 weeks for successfully completed post-tests received by mail or FAX. For those taken on-line, CE statements will be immediately available upon successful completion of the post-test.

Conflict of Interest Statement: Continuing pharmaceutical education programs accredited by the University of Mississippi School of Pharmacy are for scientific and educational purposes only and do not promote any product, either directly or indirectly. Every effort is made to provide a CE program that is balanced, and based on the most current, non-biased information available.

Special note for on-line version of the lesson: As you read the lesson, you will encounter hyperlinked terms. Clicking on these links will take you to web sites that provide more information on the terms. In all instances (except tables and figures), you will be leaving the CE lesson to view material that is not considered part of the CE lesson, but nevertheless constitute information that should be helpful to you in understanding the lesson's topic.

CASE
JR is a 38-year old African American male. He has a past medical history significant for diabetes and a family history significant for cardiovascular disease. His current medication regimen includes Humulin N 15 units every morning and 20 units every evening. He takes no other medications. JR’s last hemoglobin A1C was 6.4% one month ago. His current body mass index is 34 kg/m2. JR’s seated blood pressures today are 140/96 mm Hg and 142/94 mm Hg. His blood pressure was 146/90 mm Hg on a previous visit. JR smokes one-half pack cigarettes per day and drinks alcohol on special occasions. He states he smoked his last cigarette 2 hours ago. He reports feeling much better since his blood sugar has reached goal.

INTRODUCTION
Approximately 50 million people in the United States have hypertension, defined as blood pressure > 140/90 mm Hg. Previous studies have identified the relationship between blood pressure and risk of cardiovascular events. This relationship is continuous, consistent, and independent of other risk factors. Individuals treated for hypertension have significantly higher instances of cardiovascular complications than normotensive individuals. Perhaps this is due to failure in achieving normotensive levels or to residual target organ damage. With proven benefits such as a 35 to 40% reduction in stroke incidence, 20 to 25% reduction in myocardial infarction (MI), and more than 50% reduction in heart failure, emphasis on the treatment and control of hypertension is essential for controlling overall cardiovascular risk.

Hypertension control rates have improved in the last 25 years, although the current rate of 34% is still well below the goal of 50 % set by our Healthy People 2010 national objectives. According to the latest National Health and Nutrition Examination Surveys (NHANES), approximately 30 % of adults with hypertension remain undiagnosed. Released in May 2003, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) is an update of previous reports and the culmination of peer-reviewed literature published since 1997. Many of the recommendations in the previous report (JNC 6) remain unaltered, however, JNC 7 provides several new insights into the management of hypertension.

INSIGHTS FROM RECENT CLINICAL TRIALS

Since the publication of the JNC 6 in 1997, several landmark clinical trials provide evidence for the optimal management of hypertension and the prevention of associated cardiovascular events. These trials also support the inclusion of additional classes of medications as initial therapy choices in JNC 7. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is the largest hypertension trial ever conducted and perhaps the most influential. This randomized, double-blind, multicenter trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) was designed to determine whether the occurrence of fatal coronary heart disease (CHD) or nonfatal MI is lower for high-risk hypertensive patients treated with selected antihypertensive medications. This trial was designed to compare the effects of newer drug classes with a diuretic on cardiovascular outcomes. A representative from the following medication classes was selected for comparison with diuretic therapy (chlorthalidone): a calcium channel blocker (CCB, amlodipine), an angiotensin-converting enzyme inhibitor (ACEI, lisinopril), and an alpha blocker (doxazosin). In addition to the primary outcome of CHD death or nonfatal MI, secondary outcomes included all-cause mortality, fatal and non-fatal stroke, combined CHD, and combined CVD. Combined CHD represented the primary outcome, coronary revascularization, and hospitalized angina while combined CVD represented combined CHD, stroke, non-hospitalized angina, heart failure, and peripheral arterial disease.

ALLHAT consisted of 42,418 participants, men and women aged 55 years or older having stage 1 or stage 2 hypertension with at least 1 additional risk factor for adverse cardiovascular events. The doxazosin arm was terminated early after analysis reported a 25 % higher incidence of major cardiovascular events and a 100% higher incidence of heart failure compared to chlorthalidone. During a mean follow-up of 4.9 years, the primary outcome was essentially identical with the three drug classes. However, both the amlodipine and lisinopril groups had a higher risk of heart failure versus chlorthalidone (by 38% and 20%, respectively). The lisinopril group also had a higher risk of combined cardiovascular events and stroke compared with chlorthalidone. These results, combined with the relatively lower cost of chlorthalidone, led investigators to conclude that thiazide-type diuretics should be considered first-line pharmacologic therapy in patients with hypertension. This conclusion reinforced the recommendation of thiazide diuretics as first line hypertension in previous national guidelines and supported the recent JNC 7 recommendations.

Another influential study was the Heart Outcomes Prevention Evaluation (HOPE) trial. Investigators sought to determine whether the addition of ramipril would reduce the likelihood of developing cardiovascular events in high-risk patients. The trial included 9,297 participants randomized to receive ramipril 10 mg daily or placebo and Vitamin E or placebo. Participant inclusion criteria were age 55 years or older with evidence of cardiovascular disease or with diabetes and at lease one additional risk factor. The combined primary endpoint was development of MI, stroke, or cardiovascular death. Secondary endpoints included total mortality, hospital admission for congestive heart failure or unstable angina, cardiovascular revascularization, and development of overt nephropathy. The HOPE study was not a hypertension trial, participants either did not have hypertension or their hypertension was treated with other agents. Investigators found that ramipril significantly lowered the risk of the combined primary endpoint by 22 % as compared to the placebo group. Patients receiving ramipril also had significant reductions in the rate of cardiovascular death, nonfatal MI, nonfatal stroke, heart failure, revascularization, and worsening angina.

The Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE) was the first trial using an angiotensin receptor blocker (ARB) to study cardiovascular outcomes in patients with hypertension. In a double-blind, randomized, parallel-group study, investigators enrolled 9,193 individuals aged 55 to 80 years with essential hypertension and left ventricular hypertrophy (LVH). They set out to determine how angiotensin II receptor blockade with losartan compared with beta blockade using atenolol in the incidence of major cardiovascular outcomes. Losartan was found to be better than the beta blocker (BB) atenolol in reducing the combined incidence of cardiovascular death, stroke, and MI. Both stroke and new onset diabetes were also reduced by 25% in participants on losartan-based therapy. Approximately 80% of participants also required diuretic add-on therapy for blood pressure control. This highlights the need for multiple agents to achieve blood pressure control. Unlike ALLHAT, in which there were no significant differences between study drugs and primary outcomes, this study showed that losartan reduced cardiovascular morbidity and mortality more effectively than atenolol. Because blood pressure was similar in both groups throughout the trial, it is suggested that the benefits of losartan may be mediated at least in part by blood pressure independent mechanisms. This trial provides the justification for ARBs being included as an initial therapy choice for hypertension in JNC 7.

CLASSIFICATION OF BLOOD PRESSURE
Differences between the JNC 6 and JNC 7s include the classification of blood pressure for adults 18 years or older. The change in classification reflects the need for a simplified staging system as well as the results of several large-scale clinical trials published since 1997. Studies have shown that beginning at a blood pressure of 115/75 mm Hg in individuals 40 to 89 years of age, cardiovascular risk doubles with each increased increment of 20/10 mm Hg. Because of this impressive increase in the risk of cardiovascular complications associated with levels of blood pressure previously considered to be normal, a new category of blood pressure termed “prehypertension” replaces the previous high-normal classification. This change emphasizes the need for increased awareness and prevention of hypertension. The prehypertension designation includes blood pressures ranging from 120 to 139 mm Hg systolic and/or 80 to 89 mm Hg diastolic and identifies individuals at high risk for hypertension in whom adoption of healthy lifestyles could prevent or reduce the rate of progression to hypertension. Another classification change is the combination of stage 2 and 3 hypertension into a single stage 2 category, denoting blood pressures greater than or equal to 160 mm Hg systolic and/or 100 mm Hg diastolic. Table 1 provides the classification of blood pressure for adults aged 18 and older accordingly to JNC 7.

LIFESTYLE MODIFICATIONS
A healthy lifestyle is critical to reduce blood pressure, prevent or delay the incidence of hypertension, enhance antihypertensive drug efficacy, and decrease overall cardiovascular risk. Lifestyle modifications should be implemented regardless of blood pressure category. Table 2 provides a summary of lifestyle modifications with established benefits in prevention and management of hypertension.

Weight reduction in those who are overweight or obese may effectively drop systolic blood pressure by 20 mm Hg. The Dietary Approaches to Stop Hypertension (DASH) eating plan, a diet high in fruits, vegetables, and lowfat daily products with a reduced dietary cholesterol and saturated and total fat, is beneficial in decreasing blood pressure. In hypertensive patients, the effects of the DASH diet on blood pressure equal or surpass those of single-drug therapy. The diet alone may lower systolic blood pressure by as much as 14 mm Hg. Combining the DASH diet with sodium limitation provides further blood pressure benefits. In a multi-center, randomized trial, Sacks et al studied the effect of different levels of dietary sodium along with the DASH diet in both normotensive and hypertensive patients. They found that a reduction of sodium intake to levels below the current recommendation of 2400 mg substantially lowered blood pressure. In addition, decreasing sodium intake by approximately 960 mg results in a greater blood pressure decrease when the baseline sodium intake is already at the recommended level than when it is at a higher level. These results indicate there may be additional benefit in lowering the goal for dietary sodium intake. For this reason, patients should consider both dietary modifications, the DASH eating plan and sodium reduction, as viable therapeutic options for lowering blood pressure.

A combination of two lifestyle modifications increases benefits more than any single modification. Exercise can decrease blood pressure by as much as 9 mm Hg. Limiting alcohol intake to no more than 2 drinks per day for most men and 1 drink per day for women (24 oz beer or 10 oz wine), adds additional improvements to blood pressure control. Smoking cessation should be encouraged for overall cardiovascular risk reduction. Smoking increases the risk for cardiovascular events and hinders the ability to sustain exercise activities.

INITIATION OF THERAPY
In comparison with other classes of antihypertensive agents, diuretics have been virtually unsurpassed in preventing the cardiovascular complications of hypertension. Because of this, JNC 7 recommends that thiazide-type diuretics should be the preferred initial agent in most patients with hypertension. Thiazide-type diuretics may be utilized as monotherapy or in combination with other recommended drug classes (ACEI, ARB, BB, and CCB). Each of these drug classes has demonstrated benefits in cardiovascular protection in randomized clinical trials. Combination therapy should be considered initially in individuals whose blood pressure is 20/10 mm Hg above goal. There are many combination products available containing thiazide diuretics. Combination products may decrease cost to the patient and improve adherence. Despite the abundance of clinical evidence, thiazide-type diuretics are probably not used as often as they should be.

In JNC 6, direct-acting vasodilators, central alpha-2 agonists, and peripheral adrenergic antagonists were discouraged as initial monotherapy due to adverse effects. There is very little mention of these agents in JNC 7, probably due to the overwhelming evidence available for the newer agents. Utilization of direct-acting vasodilators, central alpha 2 agonists, and peripheral adrenergic antagonists should be reserved for those patients not responding to combinations of the initial recommended agents. Table 1 includes recommendations for the initial management of hypertension.

FOLLOW-UP AND MONITORING
JNC 7 recommends that most patients be evaluated monthly until goal blood pressure is achieved. Patients with stage 2 hypertension or with co-morbid conditions may require more frequent visits. Once blood pressure reaches goal, follow-up visits can usually be at 3 to 6 month intervals. Serum creatinine and potassium should be monitored at least one to two times per year. Other co-morbidities and associated diseases may influence the frequency of visits or laboratory tests.

SPECIAL SITUATIONS IN HYPERTENSION MANAGEMENT
Co-morbid disease states are common in patients with hypertension. When co-morbid disease states are present, special consideration should be given to the antihypertensive agent utilized. JNC 7 refers to these conditions as “compelling indications”. The compelling indication is managed in parallel with the blood pressure. Compelling indications for specific drug classes are based on benefits from outcome studies or those identified in existing clinical guidelines. Among other factors that the clinician should consider when selecting an antihypertensive agent are potential drug-drug interactions, patient tolerability of the medication, and desired blood pressure goals. Table 3 identifies recommended drugs for particular compelling indications.

The most common form of target organ damage associated with hypertension is ischemic heart disease (IHD) consisting of the acute coronary syndromes and heart failure. The drug of choice for patients with hypertension and stable angina is usually a BB. In the event of medication intolerability, a long-acting CCB may be an effective alternative. Individuals with acute coronary syndromes (unstable angina or myocardial infarction) should receive BBs or ACEIs as initial therapy. While these may be the drugs of choice in this situation, additional drugs may be necessary to achieve blood pressure control. ACEIs, BBs, and aldosterone antagonists have proven to be most beneficial in post-MI patients. The recommendations for heart failure depend on the presence of symptoms. ACEIs and BBs are recommended for asymptomatic and symptomatic individuals with ventricular dysfunction. ARBs, aldosterone antagonists, and loop diuretics are also recommended for symptomatic individuals.

Diabetes is a risk factor for the development of coronary artery disease, stroke, peripheral arterial disease, and microvascular complications, such as nephropathy and retinopathy. Seventy percent of all deaths in individuals with diabetes can be attributed to CVD. While tight glycemic control has been shown to decrease complications associated with diabetes, it has not shown to be more effective in reducing cardiovascular mortality than reduction of blood pressure. Consistent with the recommendations of the American Diabetes Association (ADA), the JNC 7 recommends a goal blood pressure of 130/80 mm Hg or lower for individuals with diabetes. ACEIs, ARBs, BBs, CCBs, and thiazide diuretics have all shown benefit in reducing CVD and stroke incidence in individuals with diabetes. In order to achieve target blood pressure, a combination of two or more of these agents is usually necessary. Because ACEIs and ARBs slow progression of diabetic nephropathy, JNC 7 and ADA recommend these classes for use in patients with type 2 diabetes and chronic kidney disease to delay the deterioration in glomerular filtration rate (GFR) and the worsening of albuminuria.

Patients with chronic kidney disease usually have hypertension. Chronic kidney disease is defined as reduced excretory function with an estimated GFR of less than 60 mL/min/1.73m² (corresponding to creatinine > 1.5 mg/dL in males and > 1.3 mg/dL in females) or the presence of albuminuria > 300 mg/d or 200 mg albumin per gram of creatinine. Treatment may require the use of three or more agents to achieve the goal blood pressure of 130/80 mm Hg or less. An ACEI or an ARB should be part of the regimen due to renal benefits mentioned previously. Unless hyperkalemia develops, a limited increase in creatinine (35% above baseline) with ACEI or ARB therapy is acceptable. Loop diuretics should be considered if the GFR falls below 30 mL/min/1.73m² (creatinine 2.5-3.0 mg/dL).

Blood pressure control rates differ across ethnic groups. The lowest blood pressure control rates are found in Mexican Americans and Native Americans. African Americans have less of a blood pressure response compared to whites when using BBs, ACEIs, or ARBs as monotherapy. However, this should not limit use and combining these agents with diuretics or starting them at higher doses is usually effective in abolishing these interracial differences.

Blood pressure control rates also differ across age groups. The lowest rates of blood pressure control occur in the population age 65 years and older. The prevalence of systolic hypertension increases with age and poor systolic blood pressure control is largely responsible for the unacceptably low rates of overall blood pressure control. The majority of patients will require multiple drug therapy to attain blood pressure goals. Because many elderly individuals have widely variable blood pressure and are more likely to experience orthostatic changes, it may be advisable to initiate therapy with lower doses of medications with gradual titration.

EMPATHY, MOTIVATION, AND PATIENT ADHERENCE
For antihypertensive medications to be effective, the patient must be motivated to take the prescribed medication regularly and maintain a healthy lifestyle. Through positive reinforcement, pharmacists can contribute to the improvement of patient adherence to medication regimens. Factors contributing to lack of patient adherence may include medication costs, misunderstanding of disease or treatment, denial of illness due to lack of symptoms, perception of drugs as a signal of bad health, lack of patient involvement in development of care plan and unexpected adverse effects of medicines. Recognizing and understanding cultural differences and perceptions of health are also vital in establishing a trusting relationship with the patient and developing a patient-motivated care plan. Creating a patient-clinician partnership involves the development of a mutual respect that allows a patient to become an integral part of the management process. The patient’s understanding of the disease process must go beyond taking a medication on schedule or eating the right foods.

ROLE OF THE PHARMACIST
Pharmacists have the opportunity to make a difference in the management of hypertension by becoming disease state educators. By taking the time to counsel patients on antihypertensive medications and lifestyle modifications, pharmacists have the opportunity to establish a patient-clinician partnership. Pharmacists should be knowledgeable of current clinical trial results and guidelines used to direct antihypertensive therapy. Pharmacists can also serve as liaisons between patients and physicians by monitoring adverse effects and efficacy of medications between physician visits. Pharmacists can educate the public, particularly those at high-risk for developing hypertension, by promoting health awareness. Pharmacists can also provide evidence-based recommendations to physicians when initiating medication therapy for hypertensive individuals. Preventing hypertension may be achieved by educating patients about lifestyle modification options including smoking cessation, exercise, weight loss, and proper diet.

ROLE OF THE PATIENT
Patients should take an active role in the prevention and management of hypertension. Measuring and recording home blood pressures is beneficial to both the patient and the clinician. Patients with average home blood pressures of 135/85 mm Hg are hypertensive. Home blood pressure measurement can help the patient monitor the efficacy of antihypertensive medications and lifestyle changes. Actually tracking the effect of antihypertensive medications on blood pressure may help the patient understand the importance of medication adherence. The effects of substances such as caffeine and nicotine on blood pressure are also made more evident in home blood pressure monitoring. Home blood pressure monitoring may also be beneficial in diagnosing patients with white coat hypertension.

CONCLUSION
The JNC 7 provides several changes intended to simplify the management of hypertension. Key messages from JNC 7 include the emphasis on treatment of systolic blood pressure, the importance of addressing hypertension prevention in the prehypertensive patient, the recommendation of thiazide-type diuretics as initial treatment for most patients, the recognition of compelling indications for specific co-morbid disease states, and attention to the need for two or more drugs to achieve blood pressure goal in most patients. The guidelines are not meant to replace the judgment of the clinician, rather they are meant to provide an evidence-based framework for clinicians to consider when managing hypertensive patients. Pharmacists, as the most easily accessible health care provider, have the ability to positively affect prescribing patterns and patient adherence. In particular, pharmacists can promote JNC 7 guidelines, the initiation of lifestyle modifications, and the selection of individualized drug therapy. Hypertension is still a vastly undertreated public health issue and pharmacists should be actively involved in the aggressive prevention, identification, management, and tracking of patients with hypertension.

CASE DISCUSSION
Although tight glycemic control reduces microvascular complications of diabetes, it is blood pressure reduction that is required to prevent cardiovascular events. JR’s blood pressure has been elevated on two consecutive clinic visits. Treatment of his blood pressure will require education in nonpharmacologic modalities as well as pharmacologic therapeutics. Lifestyle modification is crucial in this patient to reduce morbidity and mortality. JR should be instructed in the value of dietary changes and exercise programs to improve blood pressure control and to promote weight loss. He should also be advised of the benefits of dietary changes in management of diabetes and hyperlipidemia. JR should also be encouraged to quit smoking and limit his alcohol intake. Initiation of medication therapy for JR lends itself to several options. A thiazide-type diuretic may be beneficial as initial therapy with a target blood pressure goal of lower than 130/80 mm Hg, and optimally as close to 120/80 mm Hg as possible. A second antihypertensive agent should be added if the blood pressure goal is not achieved. If laboratory assessment identifies proteinuria or chronic kidney disease, an ACEI or ARB should be used. In the treatment of hypertension, it is necessary to address all modifiable cardiovascular factors. This would include lipid assessment in JR and appropriate management. JR should also be encouraged to monitor his blood pressure and be an active participant in all therapy decisions.

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REFERENCES
Chobanian AV, Bakris GB, Black HR et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The JNC 7. JAMA. . 2003; 289:2560-2572.

Joint National Committee on Prevention Detection, Evaluation, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997; 157:2413-2446.

Sacks FM, Svetkey SP, Vollmer WM et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med. 2001; 344:3-10.

The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA 2002; 288:2981-2997.

The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342:145-153.