Medical Education Library

• Sickle cell disease: Gaining control over the pain
• Treating herpes zoster and postherpetic neuralgia: An evidence-based approach
• Managing chronic pain in older adults: 6 steps to overcoming medication barriers

• Sickle cell disease: Gaining control over the pain
• Treating herpes zoster and postherpetic neuralgia: An evidence-based approach
• Managing chronic pain in older adults: 6 steps to overcoming medication barriers

• Sickle cell disease: Gaining control over the pain
• Treating herpes zoster and postherpetic neuralgia: An evidence-based approach
• Managing chronic pain in older adults: 6 steps to overcoming medication barriers

The Institute of Medicine (IOM) published a consensus report in June 2011 on the “national challenge” of chronic pain.¹ Below the heading “Underlying Principles,” the report states,

“Given chronic pain’s diverse effects, interdisciplinary assessment and treatment may produce the best results for people with the most severe and persistent pain problems.” ¹

Yet much of the medical community tends to treat pain as a physical problem with pharmacologic solutions, effectively dismissing the value of interdisciplinary pain management and the biopsychosocial model underlying this approach, even though its interrelated factors are clearly linked to improved physical symptoms and decreased use of costly medical resources.^2,3 However, over the past 2 decades an undeniable body of evidence favoring an interdisciplinary approach has been growing.

Rationale and research

Success with a multimodal approach to pain management has been demonstrated for a number of pain conditions, perhaps most clearly in studies of chronic low back pain (LBP). In one study, 108 patients (63% with LBP) underwent multiple sessions of individual cognitive behavioral therapy (CBT), physical therapy, aquatic physical therapy, occupational therapy, group education, and group relaxation.⁴ At program enrollment, program completion, and long-term follow-up, researchers gathered data on changes in pain severity, emotional stress, interference of pain on functioning, perceived control of pain, helpfulness of treatment, and hours resting. At 6 months and 1 year following completion of the study, all 6 measures showed statistically significant improvement over baseline, with 95% confidence intervals in 5 of the 6 showing no overlap between pre-program and follow-up measures. [TABLE 1]

TABLE 1:   Variance of outcomes of a comprehensive pain management program with 1-year follow-up (n=46) 

* No overlap in confidence interval between pretreatment and either posttreatment or 1-year scores

**n=40

Source: Adapted with permission from Oslund S, et al. Long-term effectiveness of a comprehensive pain management program: strengthening the case for interdisciplinary care. Proc (Bayl Univ Med Cent). 2009;22(3)211-214.

In a systematic review of 10 randomized controlled trials encompassing 1964 patients with disabling LBP, researchers found strong evidence that intensive multidisciplinary biopsychosocial rehabilitation improves function when compared with inpatient or outpatient treatments. The review also found moderate evidence of pain reduction with multidisciplinary care compared with non-multidisciplinary care.⁵

Studies of musculoskeletal pain also have reported good results with interdisciplinary care. In a study of interdisciplinary pain management for chronic musculoskeletal pain, military personnel were to receive either interdisciplinary care with physical therapy, occupational therapy, and psychosocial intervention, or standard anesthesia treatment alone.⁶ At 6 months and 1 year, data collected on pain, disability, functional status, and fitness for return to duty showed that interdisciplinary care was far superior to standard care.

A systematic review of randomized controlled trials found strong evidence that multidisciplinary care is more effective for nonmalignant chronic pain diagnoses (chronic LBP, back pain, fibromyalgia, and mixed chronic pain) than standard medical treatment, and moderate evidence for its effectiveness compared with other nonmultidisciplinary treatments.⁷ According to the study authors, the data support, at minimum, offering a range of treatments—including individual exercising, training in relaxation techniques, group therapy with a clinical psychologist, patient education, physiotherapy, and medical training therapy—and providing neurophysiology information. They also point out that no particular combination or duration of therapy has proved superior to others in clinical outcomes.

Risks of interdisciplinary care versus standard care

Therapies employed in interdisciplinary pain management are relatively low-risk compared with other interventions, such as opioid use or surgery. A 2010 Cochrane review of opioid use for chronic non-cancer pain found that concerns about long-term use of opioids can present a potential barrier to treatment. Opioids often lead to adverse effects (gastrointestinal effects such as constipation and nausea; headache; fatigue; urinary complications) severe enough to warrant discontinuation.8 This review found the rate of opioid addiction in these study populations was extremely low, however, and concluded that potential iatrogenic opioid addiction should not be a barrier for well-selected and well-supervised patients. As this study indicates, patients who gain pain relief from prescribed opioids might become drug dependent, but will not become addicted.

Also, although opioids are widely used,their ability to control pain varies. A study from the Mayo Comprehensive Rehabilitation Center of 233 consecutively enrolled patients with chronic nonmalignant pain found 48% were using opioids daily at baseline, at a cost of $23.13 per day or $8326.90 per year (average wholesale price) per patient.⁹ Patients who completed a 3-week multidisciplinary intervention significantly reduced their medication use at 6-month follow-up, for an estimated annual savings of $2404.80 per patient.

Two studies comparing interdisciplinary care with spine fusion surgery for chronic back pain found interdisciplinary care to be a reasonable alternative for many patients. In a study of patients with chronic LBP who had previous surgery for disc herniation, spinal fusion showed no benefit over cognitive intervention and exercise after 1 year.¹⁰ [TABLE 2] A multicenter trial comparing surgical stabilization of the lumbar spine with an intensive rehabilitation program based on CBT found no clear evidence that spinal fusion provided greater benefit.¹¹

TABLE 2 : Primary and secondary outcomes comparing spinal
fusion with CBT and exercise

*Oswestry Disability Questionnaire in which the sum of response scores ranges from 0 to 100,where 100 represents the worst possible pain and disability.

**Based on a vertical visual analog scale ranging from 0 to 100, where 100 reflected the worst pain imaginable.

Source: Adapted from Brox JI, et al. Lumbar instrumented fusion compared with cognitive intervention and exercises in patients with chronic back pain after previous surgery for disc herniation: A prospective randomized controlled study. Pain. 2006;122(1):145-155. This table has been reproduced with permission of the International Association for the Study of Pain® (IASP®). The table

may not be reproduced for any other purpose without permission.

What interdisciplinary pain management looks like

Key disciplines of an interdisciplinary pain management program are medicine, psychology, and rehabilitation. However, programs vary in available services and professional disciplines, setting, and duration. A fully integrated pain treatment center offers a range of therapies that may include transcutaneous electrical nerve stimulation, CBT, biofeedback, physical therapy, psychoeducational group treatment, and medications such as nonnarcotic analgesics and nerve blocks. Additional disciplines may include outcome database managers, vocational specialists, nutrition, case management, nursing, chaplaincy, and other disciplines an individual patient may need.

Patients should be evaluated by a pain medicine specialist and a behavioral medicine specialist. Treatment recommendations should include a structured curriculum including education, CBT, and physical therapy to address fear avoidance behavior, medication use, disability, affective distress, health care overutilization, quality of life, activities of daily living, and other patient-centric goals of rehabilitation. The interdisciplinary treatment team should be housed in the same facility and meet at least once per week to discuss new and existing patients and monitor progress toward outcome goals.

At our clinic, the Eugene McDermott Center for Pain Management at the University of Texas Southwestern Medical Center in Dallas, each patient undergoes consecutive evaluations by a pain physician, psychologist, physical therapist, and perhaps a psychiatrist. A case manager helps patients navigate through the evaluation and treatment process. At weekly case conferences, the team meets to discuss new patients, review the progress of current patients, and reinforce or modify treatment plans.

Individualizing goals

“Among steps to improving care, health-care providers should increasingly aim at tailoring pain care to each person’s experience and self-management of pain should be promoted.”¹

Pain influences and inhibits numerous areas of a patient’s life. For many chronic pain patients, duration of pain brings with it the belief that “hurt equals harm.” As a result, they decrease physical activities, become socially isolated, and often feel unable to effectively manage, control, and conquer their pain. The longer chronic pain endures, the more deleterious the psychosocial consequences, even if pain and dysfunction do not worsen.

Chronic pain causes patients to feel a domino effect of psychological and cognitive disturbances including anxiety, depression, anger, and sleep disturbance. Disability caused by pain may bring on economic and domestic difficulties. Relationships can suffer, in part because it is hard for others to understand the impact of pain, especially when there is no obvious pathology.

Part of the evaluation process is to assess these possibilities and to address them in a concerted way. We encourage patients to focus on making progress toward their treatment goals rather than hoping to find a definitive cure for a pain generator that may or may not be identifiable. Therefore, in addition to the standard outcomes we aim for with each patient (eg, improvement in physical and psychological function measures), we establish individual treatment goals based on the initial interviews and the patient’s desire to return to work, get into vocational retraining or education, or achieve other productivity or recreational outcomes.

Patients typically receive 8 to 10 sessions of CBT, with each session covering a topic such as sleep hygiene, assertiveness training, anger management, or controlling automatic thoughts that lead to catastrophization or fear of the pain getting worse.

At our center we spend an hour educating patients about pain medications, explaining how they work and why some pose risks. Patients undergo 6 to 8 sessions of physical therapy and graded exercise, starting slow and gradually building to a level that does not aggravate their pain. Teaching them correct posture and how to lift objects also is important.

Planning for long-term success

Pain management takes place on numerous levels that incorporate self care, primary care, specialty care, and the multimodal care of interdisciplinary pain centers. To avoid relapse after patients have been treated at an interdisciplinary pain center, it is important that they have a clear idea of how to proceed with their individualized programs in a self-directed manner. Those who do well in the program and return to work or the home environment may be vulnerable to stressors that can lead to relapse.

Patients who fear they cannot control the pain or that they may do something to worsen it are at risk of becoming depressed, dependent, or guarded in their activities.¹² Our program is developing a system to monitor patients more closely after they finish their program to identify those who may be spiraling downward. Patients are invited to return at any time for “booster” sessions.

Primary care involvement can strengthen patient resolve

“Also, primary care physicians—who handle most front-line pain care—should collaborate with pain specialists in cases where pain persists.”¹

The degree to which primary care physicians (PCPs) want to be involved with chronic pain management varies, of course. Interdisciplinary programs should explore the comfort level of individual providers and work with them accordingly—at the very least communicating with and including the PCP in the patient’s process so that he or she understands what the patient has encountered and achieved.¹³ This collaborative approach enables PCPs to motivate patients to continue the progress they’ve made, reinforce the biopsychosocial model for treating pain, and communicate with the interdisciplinary team about patients who may be relapsing.

Barriers to interdisciplinary care

“System and organizational barriers, many of them driven by current reimbursement policies, obstruct patient-centered care.”¹

The IOM has estimated the direct and indirect costs of pain in America to be over a half a trillion dollars per year. The potential for interdisciplinary pain care to contribute to national deficit reduction is real and is not limited to chronic pain. In fact, the application of interdisciplinary evaluations and treatment to acute and subacute pain may be more important to reduce costs related to preventing high-risk patients from becoming chronic.

A cost-utility analysis of 994 patients in pain clinics with acute back pain at high risk of becoming chronic who were provided early intervention with an interdisciplinary approach resulted in fewer health care visits and fewer missed days of work compared with patients who received usual care.¹⁴

Additional cost savings could be realized by routinely applying the biopsychosocial model to acute and subacute pain. Through well-developed evaluation systems, we could identify patients at high risk of progressing to chronicity. Screening for risk stratification is key to reducing the large number of chronic pain patients who are overmedicated, disabled, and depressed. Just as it makes sense to reduce individuals’ cardiac risk factors and not wait until they are in heart failure to act, employing a comprehensive interdisciplinary program for acute pain would be less expensive than waiting to treat pain that has become chronic.

However, only some insurers cover use of interdisciplinary pain programs, often to a limited extent, and may employ carve outs for specific therapies. Medicare does not reimburse well for interdisciplinary treatment. Consequently, many programs are paid through worker’s compensation. It is therefore challenging for interdisciplinary programs to remain viable.

Further benefits to the wider community

Our current health care system in the United States is not financially sustainable. To help curtail overutilization of health care resources in this country, we have to acknowledge psychosocial issues and embrace interdisciplinary pain programs when treating patients with pain. But it will take time and a huge cultural change for this to happen.

The future may require a combination of interdisciplinary treatment with a strong component of analgesic treatments rather than an “all or none” approach in which patients receive either “behavioral” treatment or “medical” treatment only. By definition, interdisciplinary pain treatment requires medicine as a discipline to reduce pain using everything medicine has to offer to accomplish this end.

Helpful information for you and your patients

The American Academy of Pain Management (AAPM) offers professional credentialing in pain management and accredits pain management clinics in the United States. You may be able to locate a specialist or clinic in your area at the academy’s Web site: https://members.aapainmanage.org/aapmssa/censsacustlkup.query_page.

Disclosures

Carl Noe, MD, has served as a consultant to Palladian Partners, Inc., a health communications and services company.

Charles F. Williams has no conflicts of interest to disclose.

The Institute of Medicine (IOM) published a consensus report in June 2011 on the “national challenge” of chronic pain.¹ Below the heading “Underlying Principles,” the report states,

“Given chronic pain’s diverse effects, interdisciplinary assessment and treatment may produce the best results for people with the most severe and persistent pain problems.” ¹

Yet much of the medical community tends to treat pain as a physical problem with pharmacologic solutions, effectively dismissing the value of interdisciplinary pain management and the biopsychosocial model underlying this approach, even though its interrelated factors are clearly linked to improved physical symptoms and decreased use of costly medical resources.^2,3 However, over the past 2 decades an undeniable body of evidence favoring an interdisciplinary approach has been growing.

Rationale and research

Success with a multimodal approach to pain management has been demonstrated for a number of pain conditions, perhaps most clearly in studies of chronic low back pain (LBP). In one study, 108 patients (63% with LBP) underwent multiple sessions of individual cognitive behavioral therapy (CBT), physical therapy, aquatic physical therapy, occupational therapy, group education, and group relaxation.⁴ At program enrollment, program completion, and long-term follow-up, researchers gathered data on changes in pain severity, emotional stress, interference of pain on functioning, perceived control of pain, helpfulness of treatment, and hours resting. At 6 months and 1 year following completion of the study, all 6 measures showed statistically significant improvement over baseline, with 95% confidence intervals in 5 of the 6 showing no overlap between pre-program and follow-up measures. [TABLE 1]

TABLE 1:   Variance of outcomes of a comprehensive pain management program with 1-year follow-up (n=46) 

* No overlap in confidence interval between pretreatment and either posttreatment or 1-year scores

**n=40

Source: Adapted with permission from Oslund S, et al. Long-term effectiveness of a comprehensive pain management program: strengthening the case for interdisciplinary care. Proc (Bayl Univ Med Cent). 2009;22(3)211-214.

In a systematic review of 10 randomized controlled trials encompassing 1964 patients with disabling LBP, researchers found strong evidence that intensive multidisciplinary biopsychosocial rehabilitation improves function when compared with inpatient or outpatient treatments. The review also found moderate evidence of pain reduction with multidisciplinary care compared with non-multidisciplinary care.⁵

Studies of musculoskeletal pain also have reported good results with interdisciplinary care. In a study of interdisciplinary pain management for chronic musculoskeletal pain, military personnel were to receive either interdisciplinary care with physical therapy, occupational therapy, and psychosocial intervention, or standard anesthesia treatment alone.⁶ At 6 months and 1 year, data collected on pain, disability, functional status, and fitness for return to duty showed that interdisciplinary care was far superior to standard care.

A systematic review of randomized controlled trials found strong evidence that multidisciplinary care is more effective for nonmalignant chronic pain diagnoses (chronic LBP, back pain, fibromyalgia, and mixed chronic pain) than standard medical treatment, and moderate evidence for its effectiveness compared with other nonmultidisciplinary treatments.⁷ According to the study authors, the data support, at minimum, offering a range of treatments—including individual exercising, training in relaxation techniques, group therapy with a clinical psychologist, patient education, physiotherapy, and medical training therapy—and providing neurophysiology information. They also point out that no particular combination or duration of therapy has proved superior to others in clinical outcomes.

Risks of interdisciplinary care versus standard care

Therapies employed in interdisciplinary pain management are relatively low-risk compared with other interventions, such as opioid use or surgery. A 2010 Cochrane review of opioid use for chronic non-cancer pain found that concerns about long-term use of opioids can present a potential barrier to treatment. Opioids often lead to adverse effects (gastrointestinal effects such as constipation and nausea; headache; fatigue; urinary complications) severe enough to warrant discontinuation.8 This review found the rate of opioid addiction in these study populations was extremely low, however, and concluded that potential iatrogenic opioid addiction should not be a barrier for well-selected and well-supervised patients. As this study indicates, patients who gain pain relief from prescribed opioids might become drug dependent, but will not become addicted.

Also, although opioids are widely used,their ability to control pain varies. A study from the Mayo Comprehensive Rehabilitation Center of 233 consecutively enrolled patients with chronic nonmalignant pain found 48% were using opioids daily at baseline, at a cost of $23.13 per day or $8326.90 per year (average wholesale price) per patient.⁹ Patients who completed a 3-week multidisciplinary intervention significantly reduced their medication use at 6-month follow-up, for an estimated annual savings of $2404.80 per patient.

Two studies comparing interdisciplinary care with spine fusion surgery for chronic back pain found interdisciplinary care to be a reasonable alternative for many patients. In a study of patients with chronic LBP who had previous surgery for disc herniation, spinal fusion showed no benefit over cognitive intervention and exercise after 1 year.¹⁰ [TABLE 2] A multicenter trial comparing surgical stabilization of the lumbar spine with an intensive rehabilitation program based on CBT found no clear evidence that spinal fusion provided greater benefit.¹¹

TABLE 2 : Primary and secondary outcomes comparing spinal
fusion with CBT and exercise

*Oswestry Disability Questionnaire in which the sum of response scores ranges from 0 to 100,where 100 represents the worst possible pain and disability.

**Based on a vertical visual analog scale ranging from 0 to 100, where 100 reflected the worst pain imaginable.

Source: Adapted from Brox JI, et al. Lumbar instrumented fusion compared with cognitive intervention and exercises in patients with chronic back pain after previous surgery for disc herniation: A prospective randomized controlled study. Pain. 2006;122(1):145-155. This table has been reproduced with permission of the International Association for the Study of Pain® (IASP®). The table

may not be reproduced for any other purpose without permission.

What interdisciplinary pain management looks like

Key disciplines of an interdisciplinary pain management program are medicine, psychology, and rehabilitation. However, programs vary in available services and professional disciplines, setting, and duration. A fully integrated pain treatment center offers a range of therapies that may include transcutaneous electrical nerve stimulation, CBT, biofeedback, physical therapy, psychoeducational group treatment, and medications such as nonnarcotic analgesics and nerve blocks. Additional disciplines may include outcome database managers, vocational specialists, nutrition, case management, nursing, chaplaincy, and other disciplines an individual patient may need.

Patients should be evaluated by a pain medicine specialist and a behavioral medicine specialist. Treatment recommendations should include a structured curriculum including education, CBT, and physical therapy to address fear avoidance behavior, medication use, disability, affective distress, health care overutilization, quality of life, activities of daily living, and other patient-centric goals of rehabilitation. The interdisciplinary treatment team should be housed in the same facility and meet at least once per week to discuss new and existing patients and monitor progress toward outcome goals.

At our clinic, the Eugene McDermott Center for Pain Management at the University of Texas Southwestern Medical Center in Dallas, each patient undergoes consecutive evaluations by a pain physician, psychologist, physical therapist, and perhaps a psychiatrist. A case manager helps patients navigate through the evaluation and treatment process. At weekly case conferences, the team meets to discuss new patients, review the progress of current patients, and reinforce or modify treatment plans.

Individualizing goals

“Among steps to improving care, health-care providers should increasingly aim at tailoring pain care to each person’s experience and self-management of pain should be promoted.”¹

Pain influences and inhibits numerous areas of a patient’s life. For many chronic pain patients, duration of pain brings with it the belief that “hurt equals harm.” As a result, they decrease physical activities, become socially isolated, and often feel unable to effectively manage, control, and conquer their pain. The longer chronic pain endures, the more deleterious the psychosocial consequences, even if pain and dysfunction do not worsen.

Chronic pain causes patients to feel a domino effect of psychological and cognitive disturbances including anxiety, depression, anger, and sleep disturbance. Disability caused by pain may bring on economic and domestic difficulties. Relationships can suffer, in part because it is hard for others to understand the impact of pain, especially when there is no obvious pathology.

Part of the evaluation process is to assess these possibilities and to address them in a concerted way. We encourage patients to focus on making progress toward their treatment goals rather than hoping to find a definitive cure for a pain generator that may or may not be identifiable. Therefore, in addition to the standard outcomes we aim for with each patient (eg, improvement in physical and psychological function measures), we establish individual treatment goals based on the initial interviews and the patient’s desire to return to work, get into vocational retraining or education, or achieve other productivity or recreational outcomes.

Patients typically receive 8 to 10 sessions of CBT, with each session covering a topic such as sleep hygiene, assertiveness training, anger management, or controlling automatic thoughts that lead to catastrophization or fear of the pain getting worse.

At our center we spend an hour educating patients about pain medications, explaining how they work and why some pose risks. Patients undergo 6 to 8 sessions of physical therapy and graded exercise, starting slow and gradually building to a level that does not aggravate their pain. Teaching them correct posture and how to lift objects also is important.

Planning for long-term success

Pain management takes place on numerous levels that incorporate self care, primary care, specialty care, and the multimodal care of interdisciplinary pain centers. To avoid relapse after patients have been treated at an interdisciplinary pain center, it is important that they have a clear idea of how to proceed with their individualized programs in a self-directed manner. Those who do well in the program and return to work or the home environment may be vulnerable to stressors that can lead to relapse.

Patients who fear they cannot control the pain or that they may do something to worsen it are at risk of becoming depressed, dependent, or guarded in their activities.¹² Our program is developing a system to monitor patients more closely after they finish their program to identify those who may be spiraling downward. Patients are invited to return at any time for “booster” sessions.

Primary care involvement can strengthen patient resolve

“Also, primary care physicians—who handle most front-line pain care—should collaborate with pain specialists in cases where pain persists.”¹

The degree to which primary care physicians (PCPs) want to be involved with chronic pain management varies, of course. Interdisciplinary programs should explore the comfort level of individual providers and work with them accordingly—at the very least communicating with and including the PCP in the patient’s process so that he or she understands what the patient has encountered and achieved.¹³ This collaborative approach enables PCPs to motivate patients to continue the progress they’ve made, reinforce the biopsychosocial model for treating pain, and communicate with the interdisciplinary team about patients who may be relapsing.

Barriers to interdisciplinary care

“System and organizational barriers, many of them driven by current reimbursement policies, obstruct patient-centered care.”¹

The IOM has estimated the direct and indirect costs of pain in America to be over a half a trillion dollars per year. The potential for interdisciplinary pain care to contribute to national deficit reduction is real and is not limited to chronic pain. In fact, the application of interdisciplinary evaluations and treatment to acute and subacute pain may be more important to reduce costs related to preventing high-risk patients from becoming chronic.

A cost-utility analysis of 994 patients in pain clinics with acute back pain at high risk of becoming chronic who were provided early intervention with an interdisciplinary approach resulted in fewer health care visits and fewer missed days of work compared with patients who received usual care.¹⁴

Additional cost savings could be realized by routinely applying the biopsychosocial model to acute and subacute pain. Through well-developed evaluation systems, we could identify patients at high risk of progressing to chronicity. Screening for risk stratification is key to reducing the large number of chronic pain patients who are overmedicated, disabled, and depressed. Just as it makes sense to reduce individuals’ cardiac risk factors and not wait until they are in heart failure to act, employing a comprehensive interdisciplinary program for acute pain would be less expensive than waiting to treat pain that has become chronic.

However, only some insurers cover use of interdisciplinary pain programs, often to a limited extent, and may employ carve outs for specific therapies. Medicare does not reimburse well for interdisciplinary treatment. Consequently, many programs are paid through worker’s compensation. It is therefore challenging for interdisciplinary programs to remain viable.

Further benefits to the wider community

Our current health care system in the United States is not financially sustainable. To help curtail overutilization of health care resources in this country, we have to acknowledge psychosocial issues and embrace interdisciplinary pain programs when treating patients with pain. But it will take time and a huge cultural change for this to happen.

The future may require a combination of interdisciplinary treatment with a strong component of analgesic treatments rather than an “all or none” approach in which patients receive either “behavioral” treatment or “medical” treatment only. By definition, interdisciplinary pain treatment requires medicine as a discipline to reduce pain using everything medicine has to offer to accomplish this end.

Helpful information for you and your patients

The American Academy of Pain Management (AAPM) offers professional credentialing in pain management and accredits pain management clinics in the United States. You may be able to locate a specialist or clinic in your area at the academy’s Web site: https://members.aapainmanage.org/aapmssa/censsacustlkup.query_page.

Disclosures

Carl Noe, MD, has served as a consultant to Palladian Partners, Inc., a health communications and services company.

Charles F. Williams has no conflicts of interest to disclose.

The Institute of Medicine (IOM) published a consensus report in June 2011 on the “national challenge” of chronic pain.¹ Below the heading “Underlying Principles,” the report states,

“Given chronic pain’s diverse effects, interdisciplinary assessment and treatment may produce the best results for people with the most severe and persistent pain problems.” ¹

Yet much of the medical community tends to treat pain as a physical problem with pharmacologic solutions, effectively dismissing the value of interdisciplinary pain management and the biopsychosocial model underlying this approach, even though its interrelated factors are clearly linked to improved physical symptoms and decreased use of costly medical resources.^2,3 However, over the past 2 decades an undeniable body of evidence favoring an interdisciplinary approach has been growing.

Rationale and research

Success with a multimodal approach to pain management has been demonstrated for a number of pain conditions, perhaps most clearly in studies of chronic low back pain (LBP). In one study, 108 patients (63% with LBP) underwent multiple sessions of individual cognitive behavioral therapy (CBT), physical therapy, aquatic physical therapy, occupational therapy, group education, and group relaxation.⁴ At program enrollment, program completion, and long-term follow-up, researchers gathered data on changes in pain severity, emotional stress, interference of pain on functioning, perceived control of pain, helpfulness of treatment, and hours resting. At 6 months and 1 year following completion of the study, all 6 measures showed statistically significant improvement over baseline, with 95% confidence intervals in 5 of the 6 showing no overlap between pre-program and follow-up measures. [TABLE 1]

TABLE 1:   Variance of outcomes of a comprehensive pain management program with 1-year follow-up (n=46) 

* No overlap in confidence interval between pretreatment and either posttreatment or 1-year scores

**n=40

Source: Adapted with permission from Oslund S, et al. Long-term effectiveness of a comprehensive pain management program: strengthening the case for interdisciplinary care. Proc (Bayl Univ Med Cent). 2009;22(3)211-214.

In a systematic review of 10 randomized controlled trials encompassing 1964 patients with disabling LBP, researchers found strong evidence that intensive multidisciplinary biopsychosocial rehabilitation improves function when compared with inpatient or outpatient treatments. The review also found moderate evidence of pain reduction with multidisciplinary care compared with non-multidisciplinary care.⁵

Studies of musculoskeletal pain also have reported good results with interdisciplinary care. In a study of interdisciplinary pain management for chronic musculoskeletal pain, military personnel were to receive either interdisciplinary care with physical therapy, occupational therapy, and psychosocial intervention, or standard anesthesia treatment alone.⁶ At 6 months and 1 year, data collected on pain, disability, functional status, and fitness for return to duty showed that interdisciplinary care was far superior to standard care.

A systematic review of randomized controlled trials found strong evidence that multidisciplinary care is more effective for nonmalignant chronic pain diagnoses (chronic LBP, back pain, fibromyalgia, and mixed chronic pain) than standard medical treatment, and moderate evidence for its effectiveness compared with other nonmultidisciplinary treatments.⁷ According to the study authors, the data support, at minimum, offering a range of treatments—including individual exercising, training in relaxation techniques, group therapy with a clinical psychologist, patient education, physiotherapy, and medical training therapy—and providing neurophysiology information. They also point out that no particular combination or duration of therapy has proved superior to others in clinical outcomes.

Risks of interdisciplinary care versus standard care

Therapies employed in interdisciplinary pain management are relatively low-risk compared with other interventions, such as opioid use or surgery. A 2010 Cochrane review of opioid use for chronic non-cancer pain found that concerns about long-term use of opioids can present a potential barrier to treatment. Opioids often lead to adverse effects (gastrointestinal effects such as constipation and nausea; headache; fatigue; urinary complications) severe enough to warrant discontinuation.8 This review found the rate of opioid addiction in these study populations was extremely low, however, and concluded that potential iatrogenic opioid addiction should not be a barrier for well-selected and well-supervised patients. As this study indicates, patients who gain pain relief from prescribed opioids might become drug dependent, but will not become addicted.

Also, although opioids are widely used,their ability to control pain varies. A study from the Mayo Comprehensive Rehabilitation Center of 233 consecutively enrolled patients with chronic nonmalignant pain found 48% were using opioids daily at baseline, at a cost of $23.13 per day or $8326.90 per year (average wholesale price) per patient.⁹ Patients who completed a 3-week multidisciplinary intervention significantly reduced their medication use at 6-month follow-up, for an estimated annual savings of $2404.80 per patient.

Two studies comparing interdisciplinary care with spine fusion surgery for chronic back pain found interdisciplinary care to be a reasonable alternative for many patients. In a study of patients with chronic LBP who had previous surgery for disc herniation, spinal fusion showed no benefit over cognitive intervention and exercise after 1 year.¹⁰ [TABLE 2] A multicenter trial comparing surgical stabilization of the lumbar spine with an intensive rehabilitation program based on CBT found no clear evidence that spinal fusion provided greater benefit.¹¹

TABLE 2 : Primary and secondary outcomes comparing spinal
fusion with CBT and exercise

*Oswestry Disability Questionnaire in which the sum of response scores ranges from 0 to 100,where 100 represents the worst possible pain and disability.

**Based on a vertical visual analog scale ranging from 0 to 100, where 100 reflected the worst pain imaginable.

Source: Adapted from Brox JI, et al. Lumbar instrumented fusion compared with cognitive intervention and exercises in patients with chronic back pain after previous surgery for disc herniation: A prospective randomized controlled study. Pain. 2006;122(1):145-155. This table has been reproduced with permission of the International Association for the Study of Pain® (IASP®). The table

may not be reproduced for any other purpose without permission.

What interdisciplinary pain management looks like

Key disciplines of an interdisciplinary pain management program are medicine, psychology, and rehabilitation. However, programs vary in available services and professional disciplines, setting, and duration. A fully integrated pain treatment center offers a range of therapies that may include transcutaneous electrical nerve stimulation, CBT, biofeedback, physical therapy, psychoeducational group treatment, and medications such as nonnarcotic analgesics and nerve blocks. Additional disciplines may include outcome database managers, vocational specialists, nutrition, case management, nursing, chaplaincy, and other disciplines an individual patient may need.

Patients should be evaluated by a pain medicine specialist and a behavioral medicine specialist. Treatment recommendations should include a structured curriculum including education, CBT, and physical therapy to address fear avoidance behavior, medication use, disability, affective distress, health care overutilization, quality of life, activities of daily living, and other patient-centric goals of rehabilitation. The interdisciplinary treatment team should be housed in the same facility and meet at least once per week to discuss new and existing patients and monitor progress toward outcome goals.

At our clinic, the Eugene McDermott Center for Pain Management at the University of Texas Southwestern Medical Center in Dallas, each patient undergoes consecutive evaluations by a pain physician, psychologist, physical therapist, and perhaps a psychiatrist. A case manager helps patients navigate through the evaluation and treatment process. At weekly case conferences, the team meets to discuss new patients, review the progress of current patients, and reinforce or modify treatment plans.

Individualizing goals

“Among steps to improving care, health-care providers should increasingly aim at tailoring pain care to each person’s experience and self-management of pain should be promoted.”¹

Pain influences and inhibits numerous areas of a patient’s life. For many chronic pain patients, duration of pain brings with it the belief that “hurt equals harm.” As a result, they decrease physical activities, become socially isolated, and often feel unable to effectively manage, control, and conquer their pain. The longer chronic pain endures, the more deleterious the psychosocial consequences, even if pain and dysfunction do not worsen.

Chronic pain causes patients to feel a domino effect of psychological and cognitive disturbances including anxiety, depression, anger, and sleep disturbance. Disability caused by pain may bring on economic and domestic difficulties. Relationships can suffer, in part because it is hard for others to understand the impact of pain, especially when there is no obvious pathology.

Part of the evaluation process is to assess these possibilities and to address them in a concerted way. We encourage patients to focus on making progress toward their treatment goals rather than hoping to find a definitive cure for a pain generator that may or may not be identifiable. Therefore, in addition to the standard outcomes we aim for with each patient (eg, improvement in physical and psychological function measures), we establish individual treatment goals based on the initial interviews and the patient’s desire to return to work, get into vocational retraining or education, or achieve other productivity or recreational outcomes.

Patients typically receive 8 to 10 sessions of CBT, with each session covering a topic such as sleep hygiene, assertiveness training, anger management, or controlling automatic thoughts that lead to catastrophization or fear of the pain getting worse.

At our center we spend an hour educating patients about pain medications, explaining how they work and why some pose risks. Patients undergo 6 to 8 sessions of physical therapy and graded exercise, starting slow and gradually building to a level that does not aggravate their pain. Teaching them correct posture and how to lift objects also is important.

Planning for long-term success

Pain management takes place on numerous levels that incorporate self care, primary care, specialty care, and the multimodal care of interdisciplinary pain centers. To avoid relapse after patients have been treated at an interdisciplinary pain center, it is important that they have a clear idea of how to proceed with their individualized programs in a self-directed manner. Those who do well in the program and return to work or the home environment may be vulnerable to stressors that can lead to relapse.

Patients who fear they cannot control the pain or that they may do something to worsen it are at risk of becoming depressed, dependent, or guarded in their activities.¹² Our program is developing a system to monitor patients more closely after they finish their program to identify those who may be spiraling downward. Patients are invited to return at any time for “booster” sessions.

Primary care involvement can strengthen patient resolve

“Also, primary care physicians—who handle most front-line pain care—should collaborate with pain specialists in cases where pain persists.”¹

The degree to which primary care physicians (PCPs) want to be involved with chronic pain management varies, of course. Interdisciplinary programs should explore the comfort level of individual providers and work with them accordingly—at the very least communicating with and including the PCP in the patient’s process so that he or she understands what the patient has encountered and achieved.¹³ This collaborative approach enables PCPs to motivate patients to continue the progress they’ve made, reinforce the biopsychosocial model for treating pain, and communicate with the interdisciplinary team about patients who may be relapsing.

Barriers to interdisciplinary care

“System and organizational barriers, many of them driven by current reimbursement policies, obstruct patient-centered care.”¹

The IOM has estimated the direct and indirect costs of pain in America to be over a half a trillion dollars per year. The potential for interdisciplinary pain care to contribute to national deficit reduction is real and is not limited to chronic pain. In fact, the application of interdisciplinary evaluations and treatment to acute and subacute pain may be more important to reduce costs related to preventing high-risk patients from becoming chronic.

A cost-utility analysis of 994 patients in pain clinics with acute back pain at high risk of becoming chronic who were provided early intervention with an interdisciplinary approach resulted in fewer health care visits and fewer missed days of work compared with patients who received usual care.¹⁴

Additional cost savings could be realized by routinely applying the biopsychosocial model to acute and subacute pain. Through well-developed evaluation systems, we could identify patients at high risk of progressing to chronicity. Screening for risk stratification is key to reducing the large number of chronic pain patients who are overmedicated, disabled, and depressed. Just as it makes sense to reduce individuals’ cardiac risk factors and not wait until they are in heart failure to act, employing a comprehensive interdisciplinary program for acute pain would be less expensive than waiting to treat pain that has become chronic.

However, only some insurers cover use of interdisciplinary pain programs, often to a limited extent, and may employ carve outs for specific therapies. Medicare does not reimburse well for interdisciplinary treatment. Consequently, many programs are paid through worker’s compensation. It is therefore challenging for interdisciplinary programs to remain viable.

Further benefits to the wider community

Our current health care system in the United States is not financially sustainable. To help curtail overutilization of health care resources in this country, we have to acknowledge psychosocial issues and embrace interdisciplinary pain programs when treating patients with pain. But it will take time and a huge cultural change for this to happen.

The future may require a combination of interdisciplinary treatment with a strong component of analgesic treatments rather than an “all or none” approach in which patients receive either “behavioral” treatment or “medical” treatment only. By definition, interdisciplinary pain treatment requires medicine as a discipline to reduce pain using everything medicine has to offer to accomplish this end.

Helpful information for you and your patients

The American Academy of Pain Management (AAPM) offers professional credentialing in pain management and accredits pain management clinics in the United States. You may be able to locate a specialist or clinic in your area at the academy’s Web site: https://members.aapainmanage.org/aapmssa/censsacustlkup.query_page.

Disclosures

Carl Noe, MD, has served as a consultant to Palladian Partners, Inc., a health communications and services company.

Charles F. Williams has no conflicts of interest to disclose.

Although an estimated 1 out of 3 people in the United States has been diagnosed with hypertension, data from the 2007-2008 National Health and Nutrition Examination Survey found that just 72% are currently being treated and, of those, just half have their blood pressure (BP) controlled with lifestyle changes and/or medication.¹

The failure of so many people with hypertension to obtain BP control, despite the availability of numerous effective medications, is partially due to a lack of adherence to recommended treatments (eg, taking medication, following a diet, and executing lifestyle changes). Adherence is a significant problem in hypertension and evidence shows that just half of patients who initiate drug therapy are persistent with treatment after 1 year.²

Although few studies link nonadherence with long-term outcomes, 1 study found that patients who “forgot” to take their antihypertensive medication were nearly one-third more likely to experience a cardiovascular event or death (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.04-1.57).³ Adherence is important not only for the health of the patient, but also to provide overall cost savings from the reductions of hospitalizations for complications from an untreated disease.⁴

Barriers to adherence

A significant contributor to nonadherence is treatment complexity, which manifests in hypertension as pill burden. Up to 75% of patients will require more than 1 medication to control their BP; those with resistant hypertension will require 4 or more.^5,6 These medications must often be taken at different times of the day, with varying frequency.^6-9

Reducing the number of daily doses has been consistently found to enhance adherence, and should be considered routinely as a first-line strategy. Complex strategies (eg, group visits, designated office staff to assist hypertensive patients, pharmacist consultation and comanagement, exercise counseling, dietary counseling, multidisciplinary hypertension team care, specific interviewing techniques such as motivational interviewing) are promising, but individual clinicians may not have the resources to take advantage of such labor-intensive intervention. Further, when multimodal intervention is employed, it is often difficult to discern which component(s) of the intervention were most impactful, unless multifactorial study design is employed, which it rarely is. We await further randomized controlled trials in this regard.

A study of approximately 85,000 members of a large managed care organization found that the greater the number of antihypertensive medications prescribed, the lower the rate of patient adherence. Just 63% of those receiving 3-drug regimens and 55% of those receiving 4-drug regimens were completely adherent.¹⁰

In addition, many patients with hypertension, particularly older patients, have comorbid conditions (eg, dyslipidemia or diabetes) that also require treatment, leading to increased treatment complexity and pill burden.^11,12

One option for reducing pill burden is the use of fixed-dose therapies ( TABLE ). Since 2000, many new fixed-dose combinations, including at least 3 triple therapies, have entered the market.¹³ In addition, a so-called “poly-pill” that combines aspirin, 3 antihypertensives, and a statin is under investigation and demonstrating good results in reducing BP and cholesterol levels.¹⁴

TABLE

Currently available combination therapies

Studies have found that patients receiving fixed-dose combination pills are more likely to reach their target BP, physicians are more satisfied with their ability to manage hypertension, and adverse effects are either similar or less with the fixed-dose therapies compared with monotherapies.^15,16

Studies of adherence patterns among patients treated with fixed-dose combinations of antihypertensive agents vs separate antihypertensive agents demonstrate increased adherence among patients treated with fixed-dose combinations.^17-21 In a clinical trial involving 4146 participants who were treated with a fixed dose of amlodipine and atorvastatin or separate pills, 33% of patients in the fixed-dose cohort had ceased treatment by 12 months compared with 59% of patients who were taking the 2-pill regimen (HR, 2.17; 95% CI, 2.05–2.13; P < .0001), resulting in a 117% higher rate of nonadherence in the 2-pill regimen. The median persistence time (ie, time to discontinuation with medication) was 8 months with the 2-pill regimen, but 37 months or longer with the fixed-dose combination.²¹

A meta-analysis of 9 studies found that fixed-dose combinations reduced the risk of nonadherence by 26% compared with single-pill combination therapy.²²

One downside to fixed-dose therapy is cost. Out-of-pocket costs are a significant barrier to medication adherence and most fixed-dose options are branded drugs that generally require higher copayments or coinsurance vs generic single-pill drugs that may have copayments as low as $4.⁶

Other opportunities to improve adherence to antihypertensive medications

Other evidence-based opportunities to improve adherence to antihypertensive medications include improved relationships with, and communication from, health care providers, given that patients often do not understand their disease and recommended treatments.^23,24

Interviews with 826 patients with hypertension found that although 90% knew that lowering their BP would improve their health and 91% reported that a health care provider had told them that they had hypertension or high BP, 41% did not know their BP level. In addition, just 34% of patients with hypertension identified systolic BP (SBP) as the “top” number of their reading and only 32% identified diastolic BP (DBP) as the “bottom” number. Finally, only one-third of patients were able to identify both SBP and DBP, and one-quarter of them did not know the optimal level for either.²⁵

Other provider interventions that have resulted in improved adherence include changing medication to reduce or avoid adverse effects, simplifying dosing (as described earlier), and switching to less-expensive drugs if cost is an issue. Nurses and pharmacists are also important members of the team when it comes to improving adherence and reinforcing education.²⁴

Home blood pressure monitoring

Another reason for nonadherence is that patients may not believe they need treatment since hypertension rarely manifests with symptoms. Furthermore, patients may not perceive that the medication they take has any effect because they did not have symptoms to begin with. Home BP monitoring (HBPM), or self BP monitoring, is one tool for improving adherence, possibly by providing immediate feedback to patients on how well their BP is controlled.²⁶ Many major medical societies recommend HBPM as part of any hypertension management strategy.^27-30

Patients who use HBPM can avoid many limitations associated with office BP monitoring (OBPM), including poor measurement techniques, infrequent measurement, white coat hypertension, and masked hypertension. Patients can also avoid reverse white coat hypertension, where OBPM is normal although out-of-office BP is high.²⁸ Patients should take 3 readings at 1-minute intervals, usually in the morning and evening. The weekly average of these readings is their home BP (normotension is defined as an average BP <135/85 mm Hg).³¹ Typically, the HBPM monitoring is more accurate in identifying risk than OBPM when there are discrepancies between them.²⁸ It is good practice to instruct patients utilizing HBPM to bring their home BP device to the office for a comparison.

There is some evidence that HBPM may contribute to improved adherence. A systematic review of 11 randomized controlled trials found that in 6 trials the use of HBPM resulted in improved medication adherence, although in 5 of those studies additional interventions were used. These interventions included patient counseling about adverse effects of the medication, timepiece caps that reminded patients to take their medication, tips to enhance adherence, and reinforcement of positive behavior by nurses, pharmacists, lay health workers, or a telephonic system.³² This illustrates an important point in adherence interventions: more is better, and it usually takes a combination of approaches to improve adherence.^33,34

The only trial in the review that demonstrated that HBPM alone improved adherence randomized 628 patients to either HBPM or usual care for 6 weeks. The groups had similar compliance rates at baseline, and both demonstrated less adherence at the end of the 6-week trial. However, patients who measured their BP at home still demonstrated greater compliance than those receiving usual care (P < .05).³⁵

A more recent trial in 57 patients, 38 of whom measured their BP at home and 19 of whom received usual care, found greater medication adherence in the HBPM group than in the control group (100% vs 88%, P < .031). The HBPM group also reached their treatment goals significantly faster than the control group (P = .02).³⁶

Conclusion

Approximately 50% of individuals with hypertension who receive antihypertensive medication still do not reach their BP goal. One reason is nonadherence to medication, which is often related to treatment complexity, or pill burden. Given that most patients with hypertension will require more than 1 drug to manage their blood pressure, it is important that clinicians identify opportunities to simplify treatment. This may include fixed-dose combination therapy, which can improve adherence, as well as additional education regarding the efficacy and adverse effects of therapy.

The use of HBPM may also improve adherence by providing frequent feedback on treatment effectiveness.

It is important, however, that clinicians understand that no single approach to adherence will work for every patient. The greatest success comes with combining several approaches based on the barriers that affect each individual patient.

Although an estimated 1 out of 3 people in the United States has been diagnosed with hypertension, data from the 2007-2008 National Health and Nutrition Examination Survey found that just 72% are currently being treated and, of those, just half have their blood pressure (BP) controlled with lifestyle changes and/or medication.¹

The failure of so many people with hypertension to obtain BP control, despite the availability of numerous effective medications, is partially due to a lack of adherence to recommended treatments (eg, taking medication, following a diet, and executing lifestyle changes). Adherence is a significant problem in hypertension and evidence shows that just half of patients who initiate drug therapy are persistent with treatment after 1 year.²

Although few studies link nonadherence with long-term outcomes, 1 study found that patients who “forgot” to take their antihypertensive medication were nearly one-third more likely to experience a cardiovascular event or death (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.04-1.57).³ Adherence is important not only for the health of the patient, but also to provide overall cost savings from the reductions of hospitalizations for complications from an untreated disease.⁴

Barriers to adherence

A significant contributor to nonadherence is treatment complexity, which manifests in hypertension as pill burden. Up to 75% of patients will require more than 1 medication to control their BP; those with resistant hypertension will require 4 or more.^5,6 These medications must often be taken at different times of the day, with varying frequency.^6-9

Reducing the number of daily doses has been consistently found to enhance adherence, and should be considered routinely as a first-line strategy. Complex strategies (eg, group visits, designated office staff to assist hypertensive patients, pharmacist consultation and comanagement, exercise counseling, dietary counseling, multidisciplinary hypertension team care, specific interviewing techniques such as motivational interviewing) are promising, but individual clinicians may not have the resources to take advantage of such labor-intensive intervention. Further, when multimodal intervention is employed, it is often difficult to discern which component(s) of the intervention were most impactful, unless multifactorial study design is employed, which it rarely is. We await further randomized controlled trials in this regard.

A study of approximately 85,000 members of a large managed care organization found that the greater the number of antihypertensive medications prescribed, the lower the rate of patient adherence. Just 63% of those receiving 3-drug regimens and 55% of those receiving 4-drug regimens were completely adherent.¹⁰

In addition, many patients with hypertension, particularly older patients, have comorbid conditions (eg, dyslipidemia or diabetes) that also require treatment, leading to increased treatment complexity and pill burden.^11,12

One option for reducing pill burden is the use of fixed-dose therapies ( TABLE ). Since 2000, many new fixed-dose combinations, including at least 3 triple therapies, have entered the market.¹³ In addition, a so-called “poly-pill” that combines aspirin, 3 antihypertensives, and a statin is under investigation and demonstrating good results in reducing BP and cholesterol levels.¹⁴

TABLE

Currently available combination therapies

Studies have found that patients receiving fixed-dose combination pills are more likely to reach their target BP, physicians are more satisfied with their ability to manage hypertension, and adverse effects are either similar or less with the fixed-dose therapies compared with monotherapies.^15,16

Studies of adherence patterns among patients treated with fixed-dose combinations of antihypertensive agents vs separate antihypertensive agents demonstrate increased adherence among patients treated with fixed-dose combinations.^17-21 In a clinical trial involving 4146 participants who were treated with a fixed dose of amlodipine and atorvastatin or separate pills, 33% of patients in the fixed-dose cohort had ceased treatment by 12 months compared with 59% of patients who were taking the 2-pill regimen (HR, 2.17; 95% CI, 2.05–2.13; P < .0001), resulting in a 117% higher rate of nonadherence in the 2-pill regimen. The median persistence time (ie, time to discontinuation with medication) was 8 months with the 2-pill regimen, but 37 months or longer with the fixed-dose combination.²¹

A meta-analysis of 9 studies found that fixed-dose combinations reduced the risk of nonadherence by 26% compared with single-pill combination therapy.²²

One downside to fixed-dose therapy is cost. Out-of-pocket costs are a significant barrier to medication adherence and most fixed-dose options are branded drugs that generally require higher copayments or coinsurance vs generic single-pill drugs that may have copayments as low as $4.⁶

Other opportunities to improve adherence to antihypertensive medications

Other evidence-based opportunities to improve adherence to antihypertensive medications include improved relationships with, and communication from, health care providers, given that patients often do not understand their disease and recommended treatments.^23,24

Interviews with 826 patients with hypertension found that although 90% knew that lowering their BP would improve their health and 91% reported that a health care provider had told them that they had hypertension or high BP, 41% did not know their BP level. In addition, just 34% of patients with hypertension identified systolic BP (SBP) as the “top” number of their reading and only 32% identified diastolic BP (DBP) as the “bottom” number. Finally, only one-third of patients were able to identify both SBP and DBP, and one-quarter of them did not know the optimal level for either.²⁵

Other provider interventions that have resulted in improved adherence include changing medication to reduce or avoid adverse effects, simplifying dosing (as described earlier), and switching to less-expensive drugs if cost is an issue. Nurses and pharmacists are also important members of the team when it comes to improving adherence and reinforcing education.²⁴

Home blood pressure monitoring

Another reason for nonadherence is that patients may not believe they need treatment since hypertension rarely manifests with symptoms. Furthermore, patients may not perceive that the medication they take has any effect because they did not have symptoms to begin with. Home BP monitoring (HBPM), or self BP monitoring, is one tool for improving adherence, possibly by providing immediate feedback to patients on how well their BP is controlled.²⁶ Many major medical societies recommend HBPM as part of any hypertension management strategy.^27-30

Patients who use HBPM can avoid many limitations associated with office BP monitoring (OBPM), including poor measurement techniques, infrequent measurement, white coat hypertension, and masked hypertension. Patients can also avoid reverse white coat hypertension, where OBPM is normal although out-of-office BP is high.²⁸ Patients should take 3 readings at 1-minute intervals, usually in the morning and evening. The weekly average of these readings is their home BP (normotension is defined as an average BP <135/85 mm Hg).³¹ Typically, the HBPM monitoring is more accurate in identifying risk than OBPM when there are discrepancies between them.²⁸ It is good practice to instruct patients utilizing HBPM to bring their home BP device to the office for a comparison.

There is some evidence that HBPM may contribute to improved adherence. A systematic review of 11 randomized controlled trials found that in 6 trials the use of HBPM resulted in improved medication adherence, although in 5 of those studies additional interventions were used. These interventions included patient counseling about adverse effects of the medication, timepiece caps that reminded patients to take their medication, tips to enhance adherence, and reinforcement of positive behavior by nurses, pharmacists, lay health workers, or a telephonic system.³² This illustrates an important point in adherence interventions: more is better, and it usually takes a combination of approaches to improve adherence.^33,34

The only trial in the review that demonstrated that HBPM alone improved adherence randomized 628 patients to either HBPM or usual care for 6 weeks. The groups had similar compliance rates at baseline, and both demonstrated less adherence at the end of the 6-week trial. However, patients who measured their BP at home still demonstrated greater compliance than those receiving usual care (P < .05).³⁵

A more recent trial in 57 patients, 38 of whom measured their BP at home and 19 of whom received usual care, found greater medication adherence in the HBPM group than in the control group (100% vs 88%, P < .031). The HBPM group also reached their treatment goals significantly faster than the control group (P = .02).³⁶

Conclusion

Approximately 50% of individuals with hypertension who receive antihypertensive medication still do not reach their BP goal. One reason is nonadherence to medication, which is often related to treatment complexity, or pill burden. Given that most patients with hypertension will require more than 1 drug to manage their blood pressure, it is important that clinicians identify opportunities to simplify treatment. This may include fixed-dose combination therapy, which can improve adherence, as well as additional education regarding the efficacy and adverse effects of therapy.

The use of HBPM may also improve adherence by providing frequent feedback on treatment effectiveness.

It is important, however, that clinicians understand that no single approach to adherence will work for every patient. The greatest success comes with combining several approaches based on the barriers that affect each individual patient.

Although an estimated 1 out of 3 people in the United States has been diagnosed with hypertension, data from the 2007-2008 National Health and Nutrition Examination Survey found that just 72% are currently being treated and, of those, just half have their blood pressure (BP) controlled with lifestyle changes and/or medication.¹

The failure of so many people with hypertension to obtain BP control, despite the availability of numerous effective medications, is partially due to a lack of adherence to recommended treatments (eg, taking medication, following a diet, and executing lifestyle changes). Adherence is a significant problem in hypertension and evidence shows that just half of patients who initiate drug therapy are persistent with treatment after 1 year.²

Although few studies link nonadherence with long-term outcomes, 1 study found that patients who “forgot” to take their antihypertensive medication were nearly one-third more likely to experience a cardiovascular event or death (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.04-1.57).³ Adherence is important not only for the health of the patient, but also to provide overall cost savings from the reductions of hospitalizations for complications from an untreated disease.⁴

Barriers to adherence

A significant contributor to nonadherence is treatment complexity, which manifests in hypertension as pill burden. Up to 75% of patients will require more than 1 medication to control their BP; those with resistant hypertension will require 4 or more.^5,6 These medications must often be taken at different times of the day, with varying frequency.^6-9

Reducing the number of daily doses has been consistently found to enhance adherence, and should be considered routinely as a first-line strategy. Complex strategies (eg, group visits, designated office staff to assist hypertensive patients, pharmacist consultation and comanagement, exercise counseling, dietary counseling, multidisciplinary hypertension team care, specific interviewing techniques such as motivational interviewing) are promising, but individual clinicians may not have the resources to take advantage of such labor-intensive intervention. Further, when multimodal intervention is employed, it is often difficult to discern which component(s) of the intervention were most impactful, unless multifactorial study design is employed, which it rarely is. We await further randomized controlled trials in this regard.

A study of approximately 85,000 members of a large managed care organization found that the greater the number of antihypertensive medications prescribed, the lower the rate of patient adherence. Just 63% of those receiving 3-drug regimens and 55% of those receiving 4-drug regimens were completely adherent.¹⁰

In addition, many patients with hypertension, particularly older patients, have comorbid conditions (eg, dyslipidemia or diabetes) that also require treatment, leading to increased treatment complexity and pill burden.^11,12

One option for reducing pill burden is the use of fixed-dose therapies ( TABLE ). Since 2000, many new fixed-dose combinations, including at least 3 triple therapies, have entered the market.¹³ In addition, a so-called “poly-pill” that combines aspirin, 3 antihypertensives, and a statin is under investigation and demonstrating good results in reducing BP and cholesterol levels.¹⁴

TABLE

Currently available combination therapies

Studies have found that patients receiving fixed-dose combination pills are more likely to reach their target BP, physicians are more satisfied with their ability to manage hypertension, and adverse effects are either similar or less with the fixed-dose therapies compared with monotherapies.^15,16

Studies of adherence patterns among patients treated with fixed-dose combinations of antihypertensive agents vs separate antihypertensive agents demonstrate increased adherence among patients treated with fixed-dose combinations.^17-21 In a clinical trial involving 4146 participants who were treated with a fixed dose of amlodipine and atorvastatin or separate pills, 33% of patients in the fixed-dose cohort had ceased treatment by 12 months compared with 59% of patients who were taking the 2-pill regimen (HR, 2.17; 95% CI, 2.05–2.13; P < .0001), resulting in a 117% higher rate of nonadherence in the 2-pill regimen. The median persistence time (ie, time to discontinuation with medication) was 8 months with the 2-pill regimen, but 37 months or longer with the fixed-dose combination.²¹

A meta-analysis of 9 studies found that fixed-dose combinations reduced the risk of nonadherence by 26% compared with single-pill combination therapy.²²

One downside to fixed-dose therapy is cost. Out-of-pocket costs are a significant barrier to medication adherence and most fixed-dose options are branded drugs that generally require higher copayments or coinsurance vs generic single-pill drugs that may have copayments as low as $4.⁶

Other opportunities to improve adherence to antihypertensive medications

Other evidence-based opportunities to improve adherence to antihypertensive medications include improved relationships with, and communication from, health care providers, given that patients often do not understand their disease and recommended treatments.^23,24

Interviews with 826 patients with hypertension found that although 90% knew that lowering their BP would improve their health and 91% reported that a health care provider had told them that they had hypertension or high BP, 41% did not know their BP level. In addition, just 34% of patients with hypertension identified systolic BP (SBP) as the “top” number of their reading and only 32% identified diastolic BP (DBP) as the “bottom” number. Finally, only one-third of patients were able to identify both SBP and DBP, and one-quarter of them did not know the optimal level for either.²⁵

Other provider interventions that have resulted in improved adherence include changing medication to reduce or avoid adverse effects, simplifying dosing (as described earlier), and switching to less-expensive drugs if cost is an issue. Nurses and pharmacists are also important members of the team when it comes to improving adherence and reinforcing education.²⁴

Home blood pressure monitoring

Another reason for nonadherence is that patients may not believe they need treatment since hypertension rarely manifests with symptoms. Furthermore, patients may not perceive that the medication they take has any effect because they did not have symptoms to begin with. Home BP monitoring (HBPM), or self BP monitoring, is one tool for improving adherence, possibly by providing immediate feedback to patients on how well their BP is controlled.²⁶ Many major medical societies recommend HBPM as part of any hypertension management strategy.^27-30

Patients who use HBPM can avoid many limitations associated with office BP monitoring (OBPM), including poor measurement techniques, infrequent measurement, white coat hypertension, and masked hypertension. Patients can also avoid reverse white coat hypertension, where OBPM is normal although out-of-office BP is high.²⁸ Patients should take 3 readings at 1-minute intervals, usually in the morning and evening. The weekly average of these readings is their home BP (normotension is defined as an average BP <135/85 mm Hg).³¹ Typically, the HBPM monitoring is more accurate in identifying risk than OBPM when there are discrepancies between them.²⁸ It is good practice to instruct patients utilizing HBPM to bring their home BP device to the office for a comparison.

There is some evidence that HBPM may contribute to improved adherence. A systematic review of 11 randomized controlled trials found that in 6 trials the use of HBPM resulted in improved medication adherence, although in 5 of those studies additional interventions were used. These interventions included patient counseling about adverse effects of the medication, timepiece caps that reminded patients to take their medication, tips to enhance adherence, and reinforcement of positive behavior by nurses, pharmacists, lay health workers, or a telephonic system.³² This illustrates an important point in adherence interventions: more is better, and it usually takes a combination of approaches to improve adherence.^33,34

The only trial in the review that demonstrated that HBPM alone improved adherence randomized 628 patients to either HBPM or usual care for 6 weeks. The groups had similar compliance rates at baseline, and both demonstrated less adherence at the end of the 6-week trial. However, patients who measured their BP at home still demonstrated greater compliance than those receiving usual care (P < .05).³⁵

A more recent trial in 57 patients, 38 of whom measured their BP at home and 19 of whom received usual care, found greater medication adherence in the HBPM group than in the control group (100% vs 88%, P < .031). The HBPM group also reached their treatment goals significantly faster than the control group (P = .02).³⁶

Conclusion

Approximately 50% of individuals with hypertension who receive antihypertensive medication still do not reach their BP goal. One reason is nonadherence to medication, which is often related to treatment complexity, or pill burden. Given that most patients with hypertension will require more than 1 drug to manage their blood pressure, it is important that clinicians identify opportunities to simplify treatment. This may include fixed-dose combination therapy, which can improve adherence, as well as additional education regarding the efficacy and adverse effects of therapy.

The use of HBPM may also improve adherence by providing frequent feedback on treatment effectiveness.

It is important, however, that clinicians understand that no single approach to adherence will work for every patient. The greatest success comes with combining several approaches based on the barriers that affect each individual patient.

Introduction

Hypertension and hypertensive target organ damage are more prevalent and more severe in certain minority populations, especially African Americans. Hypertension is more common, more severe, develops at an earlier age, and leads to greater morbidity and mortality in African Americans than in age-matched non-Hispanic whites.¹ African Americans have among the highest rates of hypertension in the world (41% overall, 44% among black women) and develop the condition an average of 5 years earlier than whites.¹

A recent report found that although treatment rates between whites and African Americans overall are similar, a smaller percentage of African Americans with hypertension are controlled to <140/90 mm Hg compared with whites.² This may at least partly explain the 4 to 5 times higher hypertension-related mortality, 2 to 4 times increased risk of left ventricular hypertrophy (LVH), coronary heart disease (CHD), congestive heart failure, and stroke, and the 4 times higher rate of end-stage renal disease (ESRD) in African Americans compared with whites.^1,3 The higher prevalence of diabetes mellitus, cigarette smoking, obesity, lipid disorders, and LVH in blacks exacerbates the existing risk posed by hypertension, making the need for aggressive blood pressure (BP) control even more critical.¹

Antihypertensive treatment in African Americans

Lifestyle modification is recommended for all hypertensive patients but is especially important for African Americans. This population has a greater prevalence of obesity than whites, so weight loss is critical.⁴ Further, African Americans tend to have a greater sensitivity to salt because of a combination of obesity, abnormalities in renal salt handling, and a tendency to consume a high salt/low potassium diet.³ African Americans have been shown to benefit at least as much as other subgroups with hypertension from reductions in dietary salt and improvements in diet quality, such as the Dietary Approaches to Stop Hypertension (DASH) diet.^5-7

Several studies have documented the efficacy of diuretics in lowering BP in African Americans.^3,8-10 In the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT), treatment initiated with the thiazide-type diuretic (THZD) chlorthalidone (CTD) reduced systolic BP (SBP) by 4 mm Hg more than treatment based on the angiotensin-converting enzyme inhibitor (ACEI) lisinopril or the alpha-blocker doxazosin in black ALLHAT participants who were receiving similar background antihypertensive drug treatment.^9,10 The greater BP lowering in the THZD arm was associated with a significantly reduced rate in 1 or more cardiovascular disease (CVD) outcomes. Other inhibitors of the renin-angiotensin system (eg, angiotensin-receptor blockers [ARBs], direct renin inhibitors, and beta-blockers) are similarly less effective in lowering BP in African Americans.³ In contrast, when the calcium channel blocker (CCB) amlodipine was compared with CTD in blacks or when CTD was compared with lisinopril or doxazosin in nonblacks, SBP reductions were only ~1 mm Hg.^8,10

As a class, diuretics have been shown to decrease hypertension-related morbidity and mortality in both African Americans and whites.^10-15 In fact, much of the evidence for the benefits of antihypertensive therapy in preventing hypertension-related morbidity and mortality was conducted with THZDs, with several of the relevant trials containing significant numbers of African American participants (TABLE).^8,10,13-16

TABLE

Outcomes of major clinical trials of diuretics in African Americans

In the Veterans Administration (VA) Cooperative Trial, African American men comprised 42% of participants, all of whom were randomized to a combination of hydrochlorothiazide, reserpine, and hydralazine, or to placebo.¹³ In the Hypertension Detection and Follow-Up Program (HDFP) trial, 44% of participants were African American. All participants were randomized to stepped therapy with CTD, reserpine, methyldopa, and hydralazine, or to usual community care.¹⁴ Both of these pioneering trials documented the benefit of a THZD-based regimen in lowering BP and improving clinical outcomes in African Americans with hypertension. The Systolic Hypertension in the Elderly Program (SHEP) trial, in which 14% of participants were African American, extended earlier results from the VA Cooperative and HDFP trials by demonstrating that, compared with placebo, active treatment with CTD and the beta-blocker atenolol produced clinical outcome reductions in African Americans and whites with isolated systolic hypertension as well as in those with elevated diastolic BP.¹⁵

In comparative trials with newer classes of antihypertensives, THZDs have remained unsurpassed in preventing complications of hypertension, including in African Americans (TABLE). ALLHAT was the first outcome study to evaluate the relative benefit of antihypertensive treatment initiated with newer classes of antihypertensive agents vs treatment initiated with a THZD in blacks. ALLHAT included more than 15,000 African Americans and Afro-Caribbeans and confirmed the findings of studies in other populations that neither an ACEI, a CCB, or alpha-blocker–initiated therapy surpassed therapy initiated with a THZD (CTD) in lowering BP or in preventing CVD or renal outcomes.^8,10 Overall, the THZD-based therapy was superior to the alpha-blocker, ACEI, and CCB-based therapies in preventing 1 or more major forms of CVD, including stroke and heart failure (HF). In blacks, THZD-based therapy was superior to alpha-blocker–based therapy in lowering BP and in preventing overall CVD (especially HF and stroke), and was superior to the ACEI-based regimen in preventing stroke, HF, and overall CVD (a composite of CHD, stroke, and HF endpoints). Compared with CCB-based therapy (ie, amlodipine), THZD (CTD)-based therapy was similar in overall CVD protection but superior in preventing HF.

These results in ALLHAT were even more impressive in blacks with diabetes or the metabolic syndrome (TABLE).¹⁶ In addition to the above-mentioned CVD outcomes in black hypertensive patients, neither the CCB-based nor the ACEI-based regimens were superior to the THZD-based regimen in preventing ESRD overall or when stratified by diabetes or baseline estimated glomerular filtration rate.^10,16,17 In black ALLHAT participants with diabetes or the metabolic syndrome, CTD was associated with substantially reduced rates of ESRD compared with those randomized to doxazosin, amlodipine, or the ACEI lisinopril.¹⁶ It should also be noted that nearly all previous renal outcome trials with renin-angiotensin system inhibitors included background therapy with a diuretic.¹⁷

Recommendations

Most national and international guidelines recommend THZDs as first-line therapy in African Americans.^18-21 Calcium channel blockers are a reasonable alternate first-line choice in African Americans who are unable to tolerate a diuretic.

In addition, the Joint National Committee (JNC-7) guidelines recommend the use of ACEIs and ARBs as first-line therapy in all patients with hypertension comorbid with chronic kidney disease (CKD) or HF, including African Americans.¹⁸ These drugs, along with alpha-blockers and all other agents in the antihypertensive armamentarium, should be used as add-on therapy, as needed, to achieve BP goals in African Americans already receiving a THZD or CCB.

Importantly, multiple drug therapy should be considered for initial treatment in all individuals whose BP is more than 20/10 mm Hg above target.¹⁸ In addition, multiple antihypertensive agents are usually required to achieve long-term control in most patients, particularly in African Americans who, as noted earlier, tend to have more-severe hypertension.¹⁹

Conclusion

Treatment of hypertension in African Americans should include both lifestyle modifications and pharmacologic intervention, usually with multiple agents. In the absence of compelling indications for alternative therapies, THZD-based regimens should be considered first-line treatment given significant evidence from large randomized studies that document their ability to reduce both BP and hypertensive complications in this population.

Monotherapy with ACEIs, ARBs, direct renin inhibitors, or beta-blockers is less effective in lowering BP in African Americans than in other populations. ACEIs and ARBs should be included in antihypertensive regimens prescribed for African Americans with concomitant CKD or HF. They can also be considered as add-on therapy to regimens containing a THZD or CCB in the absence of these conditions.

Introduction

Hypertension and hypertensive target organ damage are more prevalent and more severe in certain minority populations, especially African Americans. Hypertension is more common, more severe, develops at an earlier age, and leads to greater morbidity and mortality in African Americans than in age-matched non-Hispanic whites.¹ African Americans have among the highest rates of hypertension in the world (41% overall, 44% among black women) and develop the condition an average of 5 years earlier than whites.¹

A recent report found that although treatment rates between whites and African Americans overall are similar, a smaller percentage of African Americans with hypertension are controlled to <140/90 mm Hg compared with whites.² This may at least partly explain the 4 to 5 times higher hypertension-related mortality, 2 to 4 times increased risk of left ventricular hypertrophy (LVH), coronary heart disease (CHD), congestive heart failure, and stroke, and the 4 times higher rate of end-stage renal disease (ESRD) in African Americans compared with whites.^1,3 The higher prevalence of diabetes mellitus, cigarette smoking, obesity, lipid disorders, and LVH in blacks exacerbates the existing risk posed by hypertension, making the need for aggressive blood pressure (BP) control even more critical.¹

Antihypertensive treatment in African Americans

Lifestyle modification is recommended for all hypertensive patients but is especially important for African Americans. This population has a greater prevalence of obesity than whites, so weight loss is critical.⁴ Further, African Americans tend to have a greater sensitivity to salt because of a combination of obesity, abnormalities in renal salt handling, and a tendency to consume a high salt/low potassium diet.³ African Americans have been shown to benefit at least as much as other subgroups with hypertension from reductions in dietary salt and improvements in diet quality, such as the Dietary Approaches to Stop Hypertension (DASH) diet.^5-7

Several studies have documented the efficacy of diuretics in lowering BP in African Americans.^3,8-10 In the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT), treatment initiated with the thiazide-type diuretic (THZD) chlorthalidone (CTD) reduced systolic BP (SBP) by 4 mm Hg more than treatment based on the angiotensin-converting enzyme inhibitor (ACEI) lisinopril or the alpha-blocker doxazosin in black ALLHAT participants who were receiving similar background antihypertensive drug treatment.^9,10 The greater BP lowering in the THZD arm was associated with a significantly reduced rate in 1 or more cardiovascular disease (CVD) outcomes. Other inhibitors of the renin-angiotensin system (eg, angiotensin-receptor blockers [ARBs], direct renin inhibitors, and beta-blockers) are similarly less effective in lowering BP in African Americans.³ In contrast, when the calcium channel blocker (CCB) amlodipine was compared with CTD in blacks or when CTD was compared with lisinopril or doxazosin in nonblacks, SBP reductions were only ~1 mm Hg.^8,10

As a class, diuretics have been shown to decrease hypertension-related morbidity and mortality in both African Americans and whites.^10-15 In fact, much of the evidence for the benefits of antihypertensive therapy in preventing hypertension-related morbidity and mortality was conducted with THZDs, with several of the relevant trials containing significant numbers of African American participants (TABLE).^8,10,13-16

TABLE

Outcomes of major clinical trials of diuretics in African Americans

In the Veterans Administration (VA) Cooperative Trial, African American men comprised 42% of participants, all of whom were randomized to a combination of hydrochlorothiazide, reserpine, and hydralazine, or to placebo.¹³ In the Hypertension Detection and Follow-Up Program (HDFP) trial, 44% of participants were African American. All participants were randomized to stepped therapy with CTD, reserpine, methyldopa, and hydralazine, or to usual community care.¹⁴ Both of these pioneering trials documented the benefit of a THZD-based regimen in lowering BP and improving clinical outcomes in African Americans with hypertension. The Systolic Hypertension in the Elderly Program (SHEP) trial, in which 14% of participants were African American, extended earlier results from the VA Cooperative and HDFP trials by demonstrating that, compared with placebo, active treatment with CTD and the beta-blocker atenolol produced clinical outcome reductions in African Americans and whites with isolated systolic hypertension as well as in those with elevated diastolic BP.¹⁵

In comparative trials with newer classes of antihypertensives, THZDs have remained unsurpassed in preventing complications of hypertension, including in African Americans (TABLE). ALLHAT was the first outcome study to evaluate the relative benefit of antihypertensive treatment initiated with newer classes of antihypertensive agents vs treatment initiated with a THZD in blacks. ALLHAT included more than 15,000 African Americans and Afro-Caribbeans and confirmed the findings of studies in other populations that neither an ACEI, a CCB, or alpha-blocker–initiated therapy surpassed therapy initiated with a THZD (CTD) in lowering BP or in preventing CVD or renal outcomes.^8,10 Overall, the THZD-based therapy was superior to the alpha-blocker, ACEI, and CCB-based therapies in preventing 1 or more major forms of CVD, including stroke and heart failure (HF). In blacks, THZD-based therapy was superior to alpha-blocker–based therapy in lowering BP and in preventing overall CVD (especially HF and stroke), and was superior to the ACEI-based regimen in preventing stroke, HF, and overall CVD (a composite of CHD, stroke, and HF endpoints). Compared with CCB-based therapy (ie, amlodipine), THZD (CTD)-based therapy was similar in overall CVD protection but superior in preventing HF.

These results in ALLHAT were even more impressive in blacks with diabetes or the metabolic syndrome (TABLE).¹⁶ In addition to the above-mentioned CVD outcomes in black hypertensive patients, neither the CCB-based nor the ACEI-based regimens were superior to the THZD-based regimen in preventing ESRD overall or when stratified by diabetes or baseline estimated glomerular filtration rate.^10,16,17 In black ALLHAT participants with diabetes or the metabolic syndrome, CTD was associated with substantially reduced rates of ESRD compared with those randomized to doxazosin, amlodipine, or the ACEI lisinopril.¹⁶ It should also be noted that nearly all previous renal outcome trials with renin-angiotensin system inhibitors included background therapy with a diuretic.¹⁷

Recommendations

Most national and international guidelines recommend THZDs as first-line therapy in African Americans.^18-21 Calcium channel blockers are a reasonable alternate first-line choice in African Americans who are unable to tolerate a diuretic.

In addition, the Joint National Committee (JNC-7) guidelines recommend the use of ACEIs and ARBs as first-line therapy in all patients with hypertension comorbid with chronic kidney disease (CKD) or HF, including African Americans.¹⁸ These drugs, along with alpha-blockers and all other agents in the antihypertensive armamentarium, should be used as add-on therapy, as needed, to achieve BP goals in African Americans already receiving a THZD or CCB.

Importantly, multiple drug therapy should be considered for initial treatment in all individuals whose BP is more than 20/10 mm Hg above target.¹⁸ In addition, multiple antihypertensive agents are usually required to achieve long-term control in most patients, particularly in African Americans who, as noted earlier, tend to have more-severe hypertension.¹⁹

Conclusion

Treatment of hypertension in African Americans should include both lifestyle modifications and pharmacologic intervention, usually with multiple agents. In the absence of compelling indications for alternative therapies, THZD-based regimens should be considered first-line treatment given significant evidence from large randomized studies that document their ability to reduce both BP and hypertensive complications in this population.

Monotherapy with ACEIs, ARBs, direct renin inhibitors, or beta-blockers is less effective in lowering BP in African Americans than in other populations. ACEIs and ARBs should be included in antihypertensive regimens prescribed for African Americans with concomitant CKD or HF. They can also be considered as add-on therapy to regimens containing a THZD or CCB in the absence of these conditions.

Introduction

Hypertension and hypertensive target organ damage are more prevalent and more severe in certain minority populations, especially African Americans. Hypertension is more common, more severe, develops at an earlier age, and leads to greater morbidity and mortality in African Americans than in age-matched non-Hispanic whites.¹ African Americans have among the highest rates of hypertension in the world (41% overall, 44% among black women) and develop the condition an average of 5 years earlier than whites.¹

A recent report found that although treatment rates between whites and African Americans overall are similar, a smaller percentage of African Americans with hypertension are controlled to <140/90 mm Hg compared with whites.² This may at least partly explain the 4 to 5 times higher hypertension-related mortality, 2 to 4 times increased risk of left ventricular hypertrophy (LVH), coronary heart disease (CHD), congestive heart failure, and stroke, and the 4 times higher rate of end-stage renal disease (ESRD) in African Americans compared with whites.^1,3 The higher prevalence of diabetes mellitus, cigarette smoking, obesity, lipid disorders, and LVH in blacks exacerbates the existing risk posed by hypertension, making the need for aggressive blood pressure (BP) control even more critical.¹

Antihypertensive treatment in African Americans

Lifestyle modification is recommended for all hypertensive patients but is especially important for African Americans. This population has a greater prevalence of obesity than whites, so weight loss is critical.⁴ Further, African Americans tend to have a greater sensitivity to salt because of a combination of obesity, abnormalities in renal salt handling, and a tendency to consume a high salt/low potassium diet.³ African Americans have been shown to benefit at least as much as other subgroups with hypertension from reductions in dietary salt and improvements in diet quality, such as the Dietary Approaches to Stop Hypertension (DASH) diet.^5-7

Several studies have documented the efficacy of diuretics in lowering BP in African Americans.^3,8-10 In the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT), treatment initiated with the thiazide-type diuretic (THZD) chlorthalidone (CTD) reduced systolic BP (SBP) by 4 mm Hg more than treatment based on the angiotensin-converting enzyme inhibitor (ACEI) lisinopril or the alpha-blocker doxazosin in black ALLHAT participants who were receiving similar background antihypertensive drug treatment.^9,10 The greater BP lowering in the THZD arm was associated with a significantly reduced rate in 1 or more cardiovascular disease (CVD) outcomes. Other inhibitors of the renin-angiotensin system (eg, angiotensin-receptor blockers [ARBs], direct renin inhibitors, and beta-blockers) are similarly less effective in lowering BP in African Americans.³ In contrast, when the calcium channel blocker (CCB) amlodipine was compared with CTD in blacks or when CTD was compared with lisinopril or doxazosin in nonblacks, SBP reductions were only ~1 mm Hg.^8,10

As a class, diuretics have been shown to decrease hypertension-related morbidity and mortality in both African Americans and whites.^10-15 In fact, much of the evidence for the benefits of antihypertensive therapy in preventing hypertension-related morbidity and mortality was conducted with THZDs, with several of the relevant trials containing significant numbers of African American participants (TABLE).^8,10,13-16

TABLE

Outcomes of major clinical trials of diuretics in African Americans

In the Veterans Administration (VA) Cooperative Trial, African American men comprised 42% of participants, all of whom were randomized to a combination of hydrochlorothiazide, reserpine, and hydralazine, or to placebo.¹³ In the Hypertension Detection and Follow-Up Program (HDFP) trial, 44% of participants were African American. All participants were randomized to stepped therapy with CTD, reserpine, methyldopa, and hydralazine, or to usual community care.¹⁴ Both of these pioneering trials documented the benefit of a THZD-based regimen in lowering BP and improving clinical outcomes in African Americans with hypertension. The Systolic Hypertension in the Elderly Program (SHEP) trial, in which 14% of participants were African American, extended earlier results from the VA Cooperative and HDFP trials by demonstrating that, compared with placebo, active treatment with CTD and the beta-blocker atenolol produced clinical outcome reductions in African Americans and whites with isolated systolic hypertension as well as in those with elevated diastolic BP.¹⁵

In comparative trials with newer classes of antihypertensives, THZDs have remained unsurpassed in preventing complications of hypertension, including in African Americans (TABLE). ALLHAT was the first outcome study to evaluate the relative benefit of antihypertensive treatment initiated with newer classes of antihypertensive agents vs treatment initiated with a THZD in blacks. ALLHAT included more than 15,000 African Americans and Afro-Caribbeans and confirmed the findings of studies in other populations that neither an ACEI, a CCB, or alpha-blocker–initiated therapy surpassed therapy initiated with a THZD (CTD) in lowering BP or in preventing CVD or renal outcomes.^8,10 Overall, the THZD-based therapy was superior to the alpha-blocker, ACEI, and CCB-based therapies in preventing 1 or more major forms of CVD, including stroke and heart failure (HF). In blacks, THZD-based therapy was superior to alpha-blocker–based therapy in lowering BP and in preventing overall CVD (especially HF and stroke), and was superior to the ACEI-based regimen in preventing stroke, HF, and overall CVD (a composite of CHD, stroke, and HF endpoints). Compared with CCB-based therapy (ie, amlodipine), THZD (CTD)-based therapy was similar in overall CVD protection but superior in preventing HF.

These results in ALLHAT were even more impressive in blacks with diabetes or the metabolic syndrome (TABLE).¹⁶ In addition to the above-mentioned CVD outcomes in black hypertensive patients, neither the CCB-based nor the ACEI-based regimens were superior to the THZD-based regimen in preventing ESRD overall or when stratified by diabetes or baseline estimated glomerular filtration rate.^10,16,17 In black ALLHAT participants with diabetes or the metabolic syndrome, CTD was associated with substantially reduced rates of ESRD compared with those randomized to doxazosin, amlodipine, or the ACEI lisinopril.¹⁶ It should also be noted that nearly all previous renal outcome trials with renin-angiotensin system inhibitors included background therapy with a diuretic.¹⁷

Recommendations

Most national and international guidelines recommend THZDs as first-line therapy in African Americans.^18-21 Calcium channel blockers are a reasonable alternate first-line choice in African Americans who are unable to tolerate a diuretic.

In addition, the Joint National Committee (JNC-7) guidelines recommend the use of ACEIs and ARBs as first-line therapy in all patients with hypertension comorbid with chronic kidney disease (CKD) or HF, including African Americans.¹⁸ These drugs, along with alpha-blockers and all other agents in the antihypertensive armamentarium, should be used as add-on therapy, as needed, to achieve BP goals in African Americans already receiving a THZD or CCB.

Importantly, multiple drug therapy should be considered for initial treatment in all individuals whose BP is more than 20/10 mm Hg above target.¹⁸ In addition, multiple antihypertensive agents are usually required to achieve long-term control in most patients, particularly in African Americans who, as noted earlier, tend to have more-severe hypertension.¹⁹

Conclusion

Treatment of hypertension in African Americans should include both lifestyle modifications and pharmacologic intervention, usually with multiple agents. In the absence of compelling indications for alternative therapies, THZD-based regimens should be considered first-line treatment given significant evidence from large randomized studies that document their ability to reduce both BP and hypertensive complications in this population.

Monotherapy with ACEIs, ARBs, direct renin inhibitors, or beta-blockers is less effective in lowering BP in African Americans than in other populations. ACEIs and ARBs should be included in antihypertensive regimens prescribed for African Americans with concomitant CKD or HF. They can also be considered as add-on therapy to regimens containing a THZD or CCB in the absence of these conditions.

Background

Despite the availability of 7 major classes of effective and safe antihypertensive medications and numerous combination drugs designed to reduce pill burden and improve adherence, just 50.1% of the estimated 76.4 million US adults with hypertension (33.5% of the population) have their condition under control.¹

One of the greatest challenges for clinicians who manage patients with hypertension is choosing the most appropriate drug, whether as initial treatment or add-on therapy. Clinicians may be guided in this decision, however, by guidelines and algorithms that are provided for hypertension management. These algorithms are reviewed in the first article in this supplement by Dr William B. White.

National guidelines recommend thiazide-type diuretics as initial therapy for most patients with hypertension, regardless of the severity of the condition, either alone or in combination with 1 of the other classes of hypertension medications that have also been shown to reduce 1 or more hypertensive complications in randomized controlled outcome trials.^2,3 These recommendations are based primarily on more than 50 years of data on the safety and efficacy of thiazide-type diuretics.

The first evidence of the benefits of thiazide-type diuretics came from publications of the VA (Veterans Administration) Cooperative Study in 1967 and 1970. It was the first trial to demonstrate reduced stroke, heart failure (HF), and progressive kidney damage in patients receiving antihypertensive treatment, including the then-newly released hydrochlorothiazide (HCTZ), a thiazide diuretic.⁴

Since then, hundreds of clinical trials have demonstrated the efficacy of thiazide-type diuretics. During that time, however, numerous other classes of antihypertensive medications were introduced, leading to the question of the appropriate place of thiazides within the antihypertensive arsenal. The seminal trial to answer this question was the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). This randomized, double-blind, multicenter, clinical trial was designed to determine whether the occurrence of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) was lower for high-risk hypertensive patients 55 years of age and older who were treated with the calcium channel blocker amlodipine, the angiotensin-converting enzyme inhibitor (ACEI) lisinopril, or the alpha-blocker doxazosin compared with the thiazide-type diuretic chlorthalidone (CTD).⁵ Investigators could add atenolol, clonidine, reserpine, and/or hydralazine as necessary to achieve blood pressure (BP) goal. The trial randomized 42,418 patients, 90% of whom had been previously treated.

At a mean follow-up of 4.9 years, there was no significant difference in the primary outcome or mortality between the 4 drugs.⁵ There was a 38% higher rate of HF with amlodipine, and a 10%, 15%, and 19% higher rate of cardiovascular disease (CVD), stroke, and HF, respectively, with lisinopril compared with CTD. For stroke, there was a statistically significant race-by-treatment interaction (40% higher stroke rate with lisinopril vs CTD in black participants). Participants in the doxazosin treatment group (n = 9061) were followed for a mean of 3.2 years. This arm was terminated early because of a 25% higher incidence of CVD events, including a nearly 2-fold higher risk of HF, accompanied by a low probability of reaching a statistically significant difference in the primary endpoint.⁵

Additional rationale for the use of diuretics in elderly populations came from the Systolic Hypertension in the Elderly Program (SHEP), a multicenter, randomized, double- blind, placebo-controlled trial of patients aged 60 years and older.⁶ Participants were randomized to either CTD 12.5 to 25 mg once daily±atenolol 25 to 50 mg once daily, or reserpine 0.05 mg once daily, or placebo. Treatment reduced the incidence of all fatal and nonfatal strokes by 36%, MI by 27%, all CHD by 27%, and all CVD by 32%.⁶

Underuse of diuretics

Despite trials such as SHEP and ALLHAT, and despite the long record of safety and efficacy in numerous patient populations, thiazide-type diuretics remain significantly under-used in clinical practice.^7-10

Even intensive academic detailing designed to increase the use of thiazide-type diuretics found that the prescribing rates of 37.1% immediately before the intervention only increased to 39.6% overall after the intervention (46.5% in areas that received the most intensive intervention), reflecting what appears to be clinical resistance to this class of drugs (FIGURE 1).¹¹ Even 4 years after the ALLHAT results were published, national use of thiazide-type drugs had not increased significantly.¹²

FIGURE 1

Proportion of visits by drug class among patients with drug-treated hypertension¹¹

Hydrochlorothiazide and chlorthalidone: Similarities and differences

Underuse of thiazide-type diuretics is just 1 challenge. Others include which diuretic to use (HCTZ or CTD) and at what dosage.^13-17 These 2 diuretics were approved at about the same time and, until recently, were considered equivalent and interchangeable despite differences in structure, pharmacokinetics, and pharmacodynamics.^16,17

The publication of the VA Cooperative Morbidity Trial, the successful marketing and popularity of HCTZ and low-dose HCTZ/triamterene, the fear of hypokalemia (which was seen more often in the high doses of CTD initially used), and the subsequent inclusion of HCTZ as the primary diuretic in single-pill combination antihypertensives with ACEIs and angiotensin II receptor blockers (ARBs) led to HCTZ becoming the market leader for this class. Nonetheless, CTD was the diuretic chosen for many major randomized clinical trials, especially those sponsored by the National Heart, Lung, and Blood Institute (NHLBI).^5,6,18-20

One reason for CTD’s relegation as a second-tier option to HCTZ could be the higher risk of hypokalemia observed at the higher dosages typically used in early studies.^21-23 However, later studies found that substantially lower dosages of CTD could provide similar BP reductions with a significantly lower risk of hypokalemia.²⁴ Materson et al,²⁵ for instance, demonstrated that the 25-mg dosage of CTD was at least as effective for hypertension as the 50-mg and 75-mg dosages, while the 25-mg dosage was associated with less hypokalemia.

Increasingly, however, hypertension specialists, particularly those involved in research, have come to appreciate that CTD and HCTZ are, indeed, not interchangeable and do not have dosing equivalency. This understanding, together with the results of clinical trials like ALLHAT, has led to a resurgence of interest in the use of CTD.^17,19,26

One assessment of outpatient prescription data from the VA from 2003 to 2008 found that although the proportion of patients receiving HCTZ during the period remained stable, the number of new users dropped 30% even as the proportion of thiazide users receiving CTD prescriptions doubled from 1.1% to 2.4% and the number of new prescriptions for CTD increased 40%.¹⁹

Chlorthalidone or hydrochlorothiazide: Study outcomes

The resurgence of interest in CTD has come with the publication of trials demonstrating its benefits in reducing CVD risk.^5,6,27,28

The Multiple Risk Factor Intervention Trial (MRFIT) is the only large, long-term, randomized trial to directly compare HCTZ and CTD, although not in a randomized assignment. The primary endpoint was cardiovascular (CV) outcomes. The study launched in 1973 and enrolled 12,866 males aged 35 to 57 years who were in the upper 15% risk of death from chronic heart disease.²⁹ Participants in the special care group were given HCTZ or CTD (investigator’s choice) at either 50 or 100 mg daily, depending on weight and sodium levels, and were given additional drugs as needed. The control group received usual care at that time from their health care provider. A 44% higher rate of CHD mortality in the HCTZ group observed towards the latter part of the trial led its Policy Advisory Board to change the option between the 2 diuretics and require CTD only. Following the change, the rate of CHD mortality decreased by 28% (P = .04 for comparison between the 2 time frames).²⁹

A recent retrospective analysis of MRFIT found significantly lower CV event rates in participants who received either CTD or HCTZ than in those receiving neither (CTD: adjusted hazard ratio [aHR], 0.51; 95% confidence interval [CI], 0.43-0.61; P < .0001; HCTZ: aHR, 0.65; 95% CI, 0.55- 0.75; P < .0001), but rates of nonfatal CV events were significantly lower in participants who received CTD than those who received HCTZ (aHR, 0.79; 95% CI, 0.68-0.92; P < .0016).³⁰ The results are depicted in FIGURE 2.³⁰

FIGURE 2

Adjusted event-free probability of cardiovascular events³⁰

Considerations for greater chlorthalidone efficacy

The differences between CTD and HCTZ, despite similar molecular structures, is a topic of much discussion.²³ It is likely that these 2 drugs have different pharmacokinetic and pharmacodynamic properties, as shown in TABLE 1.¹⁷

TABLE 1

Pharmacokinetic/pharmacodynamic comparison of hydrochlorothiazide and chlorthalidone¹⁷

	Onset (h)	Peak (h)	Half-life (h)	Duration (h)
Hydrochlorothiazide	2	4-6	6-9 (single dose) 8-15 (long-term dosing)	12 (single dose) 16-24 (long-term dosing)
Chlorthalidone	2-3	2-6	40 (single dose) 45-60 (long-term dosing)	24-48 (single dose) 48-72 (long-term dosing)
Source: Hypertension by American Heart Association; Council for High Blood Pressure Research (American Heart Association); InterAmerican Society of Hypertension. Reproduced with permission of Lippincott Williams & Wilkins in the format Journal via Copyright Clearance Center

There is also evidence from an in vitro study that, compared with HCTZ, CTD has additional pleiotropic effects: reducing carbonic anhydrase activity, platelet aggregation, and vascular permeability while promoting angiogenesis.³²

Another reason for the differences in efficacy between CTD and HCTZ could be the dosages of HCTZ used. Worldwide, nearly all prescriptions for HCTZ are for 12.5 to 25 mg/d, while most modern combination pills containing HCTZ incorporate these lower dosages.³³ However, there is little evidence that such dosages lead to significantly improved outcomes.^14,19,34-36

This was an issue in the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial. This study was designed to compare first-step therapy with benazepril/HCTZ 20/12.5 mg.³⁷ Benazepril was force-titrated to 40 mg in each arm, whereas HCTZ and amlodipine were titrated to 25 mg and 10 mg, respectively, only if needed for BP control. The study was conducted in 11,506 high-risk patients 55 years of age and older. Other antihypertensive drugs could be added as needed for BP control. The study was stopped early after a mean follow-up of 36 months when the benazepril/amlodi-pine group demonstrated an HR of 0.8 (95% CI, 0.72-0.90) for the composite outcome of death from CV events, nonfatal MI or stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization compared with the benazepril/HCTZ group.³⁷

The ACCOMPLISH trial has been controversial for many reasons, with editorials suggesting that its design led to a “stacked deck” that favored amlodipine/benazepril over benazepril/HCTZ. Questions were raised as to why HCTZ was the diuretic of choice because CTD has been used in most thiazide-type trials. The dosages chosen were also questioned because outcome trials demonstrating reduced CV events with HCTZ used target doses of 50 mg/d or higher.^14,21,22,38

Indeed, a meta-analysis published in 2011 found that despite the extensive use of HCTZ worldwide, the 12.5 to 25 mg dosage was inferior in reducing BP compared with standard doses of other antihypertensive agents (ACEIs, ARBs, beta blockers, and calcium channel blockers) in studies using 24-hour ambulatory BP monitoring.³³ The efficacy of HCTZ closely mirrors that of the other drug classes at the 50-mg level, although that dose results in somewhat higher rates of hypokalemia. As the dose of HCTZ is increased to 100 mg, there is little or no further increase in antihypertensive efficacy, but hypokalemia becomes much more common.³⁹

Thus, it can be clinically challenging to prescribe the optimum BP medication if practitioners prefer to use single-pill combinations that include HCTZ. Although the use of such single-pill combinations is warranted, particularly given the improved adherence with taking single-pill combinations compared with taking 2 or 3 pills, as noted in TABLE 1, most combinations include HCTZ dosages of 12.5 to 25 mg, which will often be less effective than full doses of 2 other medications.

Conclusion

Although thiazide-type diuretics are recommended as first-line therapy for most patients with hypertension, either alone or in combination with other classes of antihypertensives, they remain underused in clinical practice. In addition, HCTZ, which is the most commonly used diuretic (indeed, the most commonly prescribed antihypertensive) is prescribed at dosages too low to provide sufficient clinical efficacy in BP reduction and lower than what was proven to reduce CV events in clinical trials.

Chlorthalidone, a diuretic often considered a thiazide-type diuretic, has demonstrated superiority to HCTZ in reducing BP as evidenced in the MRFIT study and has been shown in numerous clinical trials to provide similar if not greater efficacy than other classes of antihypertensives in reducing BP, stroke, and CV events, with a good safety profile.

Clinicians need to manage patients with hypertension on an individual basis, selecting drugs and antihypertensive medication classes with the best outcomes in trials and then determining the most efficacious therapies with the lowest risk of adverse events for each patient. However, when prescribing a diuretic, they should also ensure that the drug used is prescribed at the appropriate therapeutic dosage level to enable patients to prevent the CV, thrombotic, and renal events that occur with long-term hypertension.

Background

Despite the availability of 7 major classes of effective and safe antihypertensive medications and numerous combination drugs designed to reduce pill burden and improve adherence, just 50.1% of the estimated 76.4 million US adults with hypertension (33.5% of the population) have their condition under control.¹

One of the greatest challenges for clinicians who manage patients with hypertension is choosing the most appropriate drug, whether as initial treatment or add-on therapy. Clinicians may be guided in this decision, however, by guidelines and algorithms that are provided for hypertension management. These algorithms are reviewed in the first article in this supplement by Dr William B. White.

National guidelines recommend thiazide-type diuretics as initial therapy for most patients with hypertension, regardless of the severity of the condition, either alone or in combination with 1 of the other classes of hypertension medications that have also been shown to reduce 1 or more hypertensive complications in randomized controlled outcome trials.^2,3 These recommendations are based primarily on more than 50 years of data on the safety and efficacy of thiazide-type diuretics.

The first evidence of the benefits of thiazide-type diuretics came from publications of the VA (Veterans Administration) Cooperative Study in 1967 and 1970. It was the first trial to demonstrate reduced stroke, heart failure (HF), and progressive kidney damage in patients receiving antihypertensive treatment, including the then-newly released hydrochlorothiazide (HCTZ), a thiazide diuretic.⁴

Since then, hundreds of clinical trials have demonstrated the efficacy of thiazide-type diuretics. During that time, however, numerous other classes of antihypertensive medications were introduced, leading to the question of the appropriate place of thiazides within the antihypertensive arsenal. The seminal trial to answer this question was the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). This randomized, double-blind, multicenter, clinical trial was designed to determine whether the occurrence of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) was lower for high-risk hypertensive patients 55 years of age and older who were treated with the calcium channel blocker amlodipine, the angiotensin-converting enzyme inhibitor (ACEI) lisinopril, or the alpha-blocker doxazosin compared with the thiazide-type diuretic chlorthalidone (CTD).⁵ Investigators could add atenolol, clonidine, reserpine, and/or hydralazine as necessary to achieve blood pressure (BP) goal. The trial randomized 42,418 patients, 90% of whom had been previously treated.

At a mean follow-up of 4.9 years, there was no significant difference in the primary outcome or mortality between the 4 drugs.⁵ There was a 38% higher rate of HF with amlodipine, and a 10%, 15%, and 19% higher rate of cardiovascular disease (CVD), stroke, and HF, respectively, with lisinopril compared with CTD. For stroke, there was a statistically significant race-by-treatment interaction (40% higher stroke rate with lisinopril vs CTD in black participants). Participants in the doxazosin treatment group (n = 9061) were followed for a mean of 3.2 years. This arm was terminated early because of a 25% higher incidence of CVD events, including a nearly 2-fold higher risk of HF, accompanied by a low probability of reaching a statistically significant difference in the primary endpoint.⁵

Additional rationale for the use of diuretics in elderly populations came from the Systolic Hypertension in the Elderly Program (SHEP), a multicenter, randomized, double- blind, placebo-controlled trial of patients aged 60 years and older.⁶ Participants were randomized to either CTD 12.5 to 25 mg once daily±atenolol 25 to 50 mg once daily, or reserpine 0.05 mg once daily, or placebo. Treatment reduced the incidence of all fatal and nonfatal strokes by 36%, MI by 27%, all CHD by 27%, and all CVD by 32%.⁶

Underuse of diuretics

Despite trials such as SHEP and ALLHAT, and despite the long record of safety and efficacy in numerous patient populations, thiazide-type diuretics remain significantly under-used in clinical practice.^7-10

Even intensive academic detailing designed to increase the use of thiazide-type diuretics found that the prescribing rates of 37.1% immediately before the intervention only increased to 39.6% overall after the intervention (46.5% in areas that received the most intensive intervention), reflecting what appears to be clinical resistance to this class of drugs (FIGURE 1).¹¹ Even 4 years after the ALLHAT results were published, national use of thiazide-type drugs had not increased significantly.¹²

FIGURE 1

Proportion of visits by drug class among patients with drug-treated hypertension¹¹

Hydrochlorothiazide and chlorthalidone: Similarities and differences

Underuse of thiazide-type diuretics is just 1 challenge. Others include which diuretic to use (HCTZ or CTD) and at what dosage.^13-17 These 2 diuretics were approved at about the same time and, until recently, were considered equivalent and interchangeable despite differences in structure, pharmacokinetics, and pharmacodynamics.^16,17

The publication of the VA Cooperative Morbidity Trial, the successful marketing and popularity of HCTZ and low-dose HCTZ/triamterene, the fear of hypokalemia (which was seen more often in the high doses of CTD initially used), and the subsequent inclusion of HCTZ as the primary diuretic in single-pill combination antihypertensives with ACEIs and angiotensin II receptor blockers (ARBs) led to HCTZ becoming the market leader for this class. Nonetheless, CTD was the diuretic chosen for many major randomized clinical trials, especially those sponsored by the National Heart, Lung, and Blood Institute (NHLBI).^5,6,18-20

One reason for CTD’s relegation as a second-tier option to HCTZ could be the higher risk of hypokalemia observed at the higher dosages typically used in early studies.^21-23 However, later studies found that substantially lower dosages of CTD could provide similar BP reductions with a significantly lower risk of hypokalemia.²⁴ Materson et al,²⁵ for instance, demonstrated that the 25-mg dosage of CTD was at least as effective for hypertension as the 50-mg and 75-mg dosages, while the 25-mg dosage was associated with less hypokalemia.

Increasingly, however, hypertension specialists, particularly those involved in research, have come to appreciate that CTD and HCTZ are, indeed, not interchangeable and do not have dosing equivalency. This understanding, together with the results of clinical trials like ALLHAT, has led to a resurgence of interest in the use of CTD.^17,19,26

One assessment of outpatient prescription data from the VA from 2003 to 2008 found that although the proportion of patients receiving HCTZ during the period remained stable, the number of new users dropped 30% even as the proportion of thiazide users receiving CTD prescriptions doubled from 1.1% to 2.4% and the number of new prescriptions for CTD increased 40%.¹⁹

Chlorthalidone or hydrochlorothiazide: Study outcomes

The resurgence of interest in CTD has come with the publication of trials demonstrating its benefits in reducing CVD risk.^5,6,27,28

The Multiple Risk Factor Intervention Trial (MRFIT) is the only large, long-term, randomized trial to directly compare HCTZ and CTD, although not in a randomized assignment. The primary endpoint was cardiovascular (CV) outcomes. The study launched in 1973 and enrolled 12,866 males aged 35 to 57 years who were in the upper 15% risk of death from chronic heart disease.²⁹ Participants in the special care group were given HCTZ or CTD (investigator’s choice) at either 50 or 100 mg daily, depending on weight and sodium levels, and were given additional drugs as needed. The control group received usual care at that time from their health care provider. A 44% higher rate of CHD mortality in the HCTZ group observed towards the latter part of the trial led its Policy Advisory Board to change the option between the 2 diuretics and require CTD only. Following the change, the rate of CHD mortality decreased by 28% (P = .04 for comparison between the 2 time frames).²⁹

A recent retrospective analysis of MRFIT found significantly lower CV event rates in participants who received either CTD or HCTZ than in those receiving neither (CTD: adjusted hazard ratio [aHR], 0.51; 95% confidence interval [CI], 0.43-0.61; P < .0001; HCTZ: aHR, 0.65; 95% CI, 0.55- 0.75; P < .0001), but rates of nonfatal CV events were significantly lower in participants who received CTD than those who received HCTZ (aHR, 0.79; 95% CI, 0.68-0.92; P < .0016).³⁰ The results are depicted in FIGURE 2.³⁰

FIGURE 2

Adjusted event-free probability of cardiovascular events³⁰

Considerations for greater chlorthalidone efficacy

The differences between CTD and HCTZ, despite similar molecular structures, is a topic of much discussion.²³ It is likely that these 2 drugs have different pharmacokinetic and pharmacodynamic properties, as shown in TABLE 1.¹⁷

TABLE 1

Pharmacokinetic/pharmacodynamic comparison of hydrochlorothiazide and chlorthalidone¹⁷

	Onset (h)	Peak (h)	Half-life (h)	Duration (h)
Hydrochlorothiazide	2	4-6	6-9 (single dose) 8-15 (long-term dosing)	12 (single dose) 16-24 (long-term dosing)
Chlorthalidone	2-3	2-6	40 (single dose) 45-60 (long-term dosing)	24-48 (single dose) 48-72 (long-term dosing)
Source: Hypertension by American Heart Association; Council for High Blood Pressure Research (American Heart Association); InterAmerican Society of Hypertension. Reproduced with permission of Lippincott Williams & Wilkins in the format Journal via Copyright Clearance Center

There is also evidence from an in vitro study that, compared with HCTZ, CTD has additional pleiotropic effects: reducing carbonic anhydrase activity, platelet aggregation, and vascular permeability while promoting angiogenesis.³²

Another reason for the differences in efficacy between CTD and HCTZ could be the dosages of HCTZ used. Worldwide, nearly all prescriptions for HCTZ are for 12.5 to 25 mg/d, while most modern combination pills containing HCTZ incorporate these lower dosages.³³ However, there is little evidence that such dosages lead to significantly improved outcomes.^14,19,34-36

This was an issue in the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial. This study was designed to compare first-step therapy with benazepril/HCTZ 20/12.5 mg.³⁷ Benazepril was force-titrated to 40 mg in each arm, whereas HCTZ and amlodipine were titrated to 25 mg and 10 mg, respectively, only if needed for BP control. The study was conducted in 11,506 high-risk patients 55 years of age and older. Other antihypertensive drugs could be added as needed for BP control. The study was stopped early after a mean follow-up of 36 months when the benazepril/amlodi-pine group demonstrated an HR of 0.8 (95% CI, 0.72-0.90) for the composite outcome of death from CV events, nonfatal MI or stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization compared with the benazepril/HCTZ group.³⁷

The ACCOMPLISH trial has been controversial for many reasons, with editorials suggesting that its design led to a “stacked deck” that favored amlodipine/benazepril over benazepril/HCTZ. Questions were raised as to why HCTZ was the diuretic of choice because CTD has been used in most thiazide-type trials. The dosages chosen were also questioned because outcome trials demonstrating reduced CV events with HCTZ used target doses of 50 mg/d or higher.^14,21,22,38

Indeed, a meta-analysis published in 2011 found that despite the extensive use of HCTZ worldwide, the 12.5 to 25 mg dosage was inferior in reducing BP compared with standard doses of other antihypertensive agents (ACEIs, ARBs, beta blockers, and calcium channel blockers) in studies using 24-hour ambulatory BP monitoring.³³ The efficacy of HCTZ closely mirrors that of the other drug classes at the 50-mg level, although that dose results in somewhat higher rates of hypokalemia. As the dose of HCTZ is increased to 100 mg, there is little or no further increase in antihypertensive efficacy, but hypokalemia becomes much more common.³⁹

Thus, it can be clinically challenging to prescribe the optimum BP medication if practitioners prefer to use single-pill combinations that include HCTZ. Although the use of such single-pill combinations is warranted, particularly given the improved adherence with taking single-pill combinations compared with taking 2 or 3 pills, as noted in TABLE 1, most combinations include HCTZ dosages of 12.5 to 25 mg, which will often be less effective than full doses of 2 other medications.

Conclusion

Although thiazide-type diuretics are recommended as first-line therapy for most patients with hypertension, either alone or in combination with other classes of antihypertensives, they remain underused in clinical practice. In addition, HCTZ, which is the most commonly used diuretic (indeed, the most commonly prescribed antihypertensive) is prescribed at dosages too low to provide sufficient clinical efficacy in BP reduction and lower than what was proven to reduce CV events in clinical trials.

Chlorthalidone, a diuretic often considered a thiazide-type diuretic, has demonstrated superiority to HCTZ in reducing BP as evidenced in the MRFIT study and has been shown in numerous clinical trials to provide similar if not greater efficacy than other classes of antihypertensives in reducing BP, stroke, and CV events, with a good safety profile.

Clinicians need to manage patients with hypertension on an individual basis, selecting drugs and antihypertensive medication classes with the best outcomes in trials and then determining the most efficacious therapies with the lowest risk of adverse events for each patient. However, when prescribing a diuretic, they should also ensure that the drug used is prescribed at the appropriate therapeutic dosage level to enable patients to prevent the CV, thrombotic, and renal events that occur with long-term hypertension.

Background

Despite the availability of 7 major classes of effective and safe antihypertensive medications and numerous combination drugs designed to reduce pill burden and improve adherence, just 50.1% of the estimated 76.4 million US adults with hypertension (33.5% of the population) have their condition under control.¹

One of the greatest challenges for clinicians who manage patients with hypertension is choosing the most appropriate drug, whether as initial treatment or add-on therapy. Clinicians may be guided in this decision, however, by guidelines and algorithms that are provided for hypertension management. These algorithms are reviewed in the first article in this supplement by Dr William B. White.

National guidelines recommend thiazide-type diuretics as initial therapy for most patients with hypertension, regardless of the severity of the condition, either alone or in combination with 1 of the other classes of hypertension medications that have also been shown to reduce 1 or more hypertensive complications in randomized controlled outcome trials.^2,3 These recommendations are based primarily on more than 50 years of data on the safety and efficacy of thiazide-type diuretics.

The first evidence of the benefits of thiazide-type diuretics came from publications of the VA (Veterans Administration) Cooperative Study in 1967 and 1970. It was the first trial to demonstrate reduced stroke, heart failure (HF), and progressive kidney damage in patients receiving antihypertensive treatment, including the then-newly released hydrochlorothiazide (HCTZ), a thiazide diuretic.⁴

Since then, hundreds of clinical trials have demonstrated the efficacy of thiazide-type diuretics. During that time, however, numerous other classes of antihypertensive medications were introduced, leading to the question of the appropriate place of thiazides within the antihypertensive arsenal. The seminal trial to answer this question was the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). This randomized, double-blind, multicenter, clinical trial was designed to determine whether the occurrence of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) was lower for high-risk hypertensive patients 55 years of age and older who were treated with the calcium channel blocker amlodipine, the angiotensin-converting enzyme inhibitor (ACEI) lisinopril, or the alpha-blocker doxazosin compared with the thiazide-type diuretic chlorthalidone (CTD).⁵ Investigators could add atenolol, clonidine, reserpine, and/or hydralazine as necessary to achieve blood pressure (BP) goal. The trial randomized 42,418 patients, 90% of whom had been previously treated.

At a mean follow-up of 4.9 years, there was no significant difference in the primary outcome or mortality between the 4 drugs.⁵ There was a 38% higher rate of HF with amlodipine, and a 10%, 15%, and 19% higher rate of cardiovascular disease (CVD), stroke, and HF, respectively, with lisinopril compared with CTD. For stroke, there was a statistically significant race-by-treatment interaction (40% higher stroke rate with lisinopril vs CTD in black participants). Participants in the doxazosin treatment group (n = 9061) were followed for a mean of 3.2 years. This arm was terminated early because of a 25% higher incidence of CVD events, including a nearly 2-fold higher risk of HF, accompanied by a low probability of reaching a statistically significant difference in the primary endpoint.⁵

Additional rationale for the use of diuretics in elderly populations came from the Systolic Hypertension in the Elderly Program (SHEP), a multicenter, randomized, double- blind, placebo-controlled trial of patients aged 60 years and older.⁶ Participants were randomized to either CTD 12.5 to 25 mg once daily±atenolol 25 to 50 mg once daily, or reserpine 0.05 mg once daily, or placebo. Treatment reduced the incidence of all fatal and nonfatal strokes by 36%, MI by 27%, all CHD by 27%, and all CVD by 32%.⁶

Underuse of diuretics

Despite trials such as SHEP and ALLHAT, and despite the long record of safety and efficacy in numerous patient populations, thiazide-type diuretics remain significantly under-used in clinical practice.^7-10

Even intensive academic detailing designed to increase the use of thiazide-type diuretics found that the prescribing rates of 37.1% immediately before the intervention only increased to 39.6% overall after the intervention (46.5% in areas that received the most intensive intervention), reflecting what appears to be clinical resistance to this class of drugs (FIGURE 1).¹¹ Even 4 years after the ALLHAT results were published, national use of thiazide-type drugs had not increased significantly.¹²

FIGURE 1

Proportion of visits by drug class among patients with drug-treated hypertension¹¹

Hydrochlorothiazide and chlorthalidone: Similarities and differences

Underuse of thiazide-type diuretics is just 1 challenge. Others include which diuretic to use (HCTZ or CTD) and at what dosage.^13-17 These 2 diuretics were approved at about the same time and, until recently, were considered equivalent and interchangeable despite differences in structure, pharmacokinetics, and pharmacodynamics.^16,17

The publication of the VA Cooperative Morbidity Trial, the successful marketing and popularity of HCTZ and low-dose HCTZ/triamterene, the fear of hypokalemia (which was seen more often in the high doses of CTD initially used), and the subsequent inclusion of HCTZ as the primary diuretic in single-pill combination antihypertensives with ACEIs and angiotensin II receptor blockers (ARBs) led to HCTZ becoming the market leader for this class. Nonetheless, CTD was the diuretic chosen for many major randomized clinical trials, especially those sponsored by the National Heart, Lung, and Blood Institute (NHLBI).^5,6,18-20

One reason for CTD’s relegation as a second-tier option to HCTZ could be the higher risk of hypokalemia observed at the higher dosages typically used in early studies.^21-23 However, later studies found that substantially lower dosages of CTD could provide similar BP reductions with a significantly lower risk of hypokalemia.²⁴ Materson et al,²⁵ for instance, demonstrated that the 25-mg dosage of CTD was at least as effective for hypertension as the 50-mg and 75-mg dosages, while the 25-mg dosage was associated with less hypokalemia.

Increasingly, however, hypertension specialists, particularly those involved in research, have come to appreciate that CTD and HCTZ are, indeed, not interchangeable and do not have dosing equivalency. This understanding, together with the results of clinical trials like ALLHAT, has led to a resurgence of interest in the use of CTD.^17,19,26

One assessment of outpatient prescription data from the VA from 2003 to 2008 found that although the proportion of patients receiving HCTZ during the period remained stable, the number of new users dropped 30% even as the proportion of thiazide users receiving CTD prescriptions doubled from 1.1% to 2.4% and the number of new prescriptions for CTD increased 40%.¹⁹

Chlorthalidone or hydrochlorothiazide: Study outcomes

The resurgence of interest in CTD has come with the publication of trials demonstrating its benefits in reducing CVD risk.^5,6,27,28

The Multiple Risk Factor Intervention Trial (MRFIT) is the only large, long-term, randomized trial to directly compare HCTZ and CTD, although not in a randomized assignment. The primary endpoint was cardiovascular (CV) outcomes. The study launched in 1973 and enrolled 12,866 males aged 35 to 57 years who were in the upper 15% risk of death from chronic heart disease.²⁹ Participants in the special care group were given HCTZ or CTD (investigator’s choice) at either 50 or 100 mg daily, depending on weight and sodium levels, and were given additional drugs as needed. The control group received usual care at that time from their health care provider. A 44% higher rate of CHD mortality in the HCTZ group observed towards the latter part of the trial led its Policy Advisory Board to change the option between the 2 diuretics and require CTD only. Following the change, the rate of CHD mortality decreased by 28% (P = .04 for comparison between the 2 time frames).²⁹

A recent retrospective analysis of MRFIT found significantly lower CV event rates in participants who received either CTD or HCTZ than in those receiving neither (CTD: adjusted hazard ratio [aHR], 0.51; 95% confidence interval [CI], 0.43-0.61; P < .0001; HCTZ: aHR, 0.65; 95% CI, 0.55- 0.75; P < .0001), but rates of nonfatal CV events were significantly lower in participants who received CTD than those who received HCTZ (aHR, 0.79; 95% CI, 0.68-0.92; P < .0016).³⁰ The results are depicted in FIGURE 2.³⁰

FIGURE 2

Adjusted event-free probability of cardiovascular events³⁰

Considerations for greater chlorthalidone efficacy

The differences between CTD and HCTZ, despite similar molecular structures, is a topic of much discussion.²³ It is likely that these 2 drugs have different pharmacokinetic and pharmacodynamic properties, as shown in TABLE 1.¹⁷

TABLE 1

Pharmacokinetic/pharmacodynamic comparison of hydrochlorothiazide and chlorthalidone¹⁷

	Onset (h)	Peak (h)	Half-life (h)	Duration (h)
Hydrochlorothiazide	2	4-6	6-9 (single dose) 8-15 (long-term dosing)	12 (single dose) 16-24 (long-term dosing)
Chlorthalidone	2-3	2-6	40 (single dose) 45-60 (long-term dosing)	24-48 (single dose) 48-72 (long-term dosing)
Source: Hypertension by American Heart Association; Council for High Blood Pressure Research (American Heart Association); InterAmerican Society of Hypertension. Reproduced with permission of Lippincott Williams & Wilkins in the format Journal via Copyright Clearance Center

There is also evidence from an in vitro study that, compared with HCTZ, CTD has additional pleiotropic effects: reducing carbonic anhydrase activity, platelet aggregation, and vascular permeability while promoting angiogenesis.³²

Another reason for the differences in efficacy between CTD and HCTZ could be the dosages of HCTZ used. Worldwide, nearly all prescriptions for HCTZ are for 12.5 to 25 mg/d, while most modern combination pills containing HCTZ incorporate these lower dosages.³³ However, there is little evidence that such dosages lead to significantly improved outcomes.^14,19,34-36

This was an issue in the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial. This study was designed to compare first-step therapy with benazepril/HCTZ 20/12.5 mg.³⁷ Benazepril was force-titrated to 40 mg in each arm, whereas HCTZ and amlodipine were titrated to 25 mg and 10 mg, respectively, only if needed for BP control. The study was conducted in 11,506 high-risk patients 55 years of age and older. Other antihypertensive drugs could be added as needed for BP control. The study was stopped early after a mean follow-up of 36 months when the benazepril/amlodi-pine group demonstrated an HR of 0.8 (95% CI, 0.72-0.90) for the composite outcome of death from CV events, nonfatal MI or stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization compared with the benazepril/HCTZ group.³⁷

The ACCOMPLISH trial has been controversial for many reasons, with editorials suggesting that its design led to a “stacked deck” that favored amlodipine/benazepril over benazepril/HCTZ. Questions were raised as to why HCTZ was the diuretic of choice because CTD has been used in most thiazide-type trials. The dosages chosen were also questioned because outcome trials demonstrating reduced CV events with HCTZ used target doses of 50 mg/d or higher.^14,21,22,38

Indeed, a meta-analysis published in 2011 found that despite the extensive use of HCTZ worldwide, the 12.5 to 25 mg dosage was inferior in reducing BP compared with standard doses of other antihypertensive agents (ACEIs, ARBs, beta blockers, and calcium channel blockers) in studies using 24-hour ambulatory BP monitoring.³³ The efficacy of HCTZ closely mirrors that of the other drug classes at the 50-mg level, although that dose results in somewhat higher rates of hypokalemia. As the dose of HCTZ is increased to 100 mg, there is little or no further increase in antihypertensive efficacy, but hypokalemia becomes much more common.³⁹

Thus, it can be clinically challenging to prescribe the optimum BP medication if practitioners prefer to use single-pill combinations that include HCTZ. Although the use of such single-pill combinations is warranted, particularly given the improved adherence with taking single-pill combinations compared with taking 2 or 3 pills, as noted in TABLE 1, most combinations include HCTZ dosages of 12.5 to 25 mg, which will often be less effective than full doses of 2 other medications.

Conclusion

Although thiazide-type diuretics are recommended as first-line therapy for most patients with hypertension, either alone or in combination with other classes of antihypertensives, they remain underused in clinical practice. In addition, HCTZ, which is the most commonly used diuretic (indeed, the most commonly prescribed antihypertensive) is prescribed at dosages too low to provide sufficient clinical efficacy in BP reduction and lower than what was proven to reduce CV events in clinical trials.

Chlorthalidone, a diuretic often considered a thiazide-type diuretic, has demonstrated superiority to HCTZ in reducing BP as evidenced in the MRFIT study and has been shown in numerous clinical trials to provide similar if not greater efficacy than other classes of antihypertensives in reducing BP, stroke, and CV events, with a good safety profile.

Clinicians need to manage patients with hypertension on an individual basis, selecting drugs and antihypertensive medication classes with the best outcomes in trials and then determining the most efficacious therapies with the lowest risk of adverse events for each patient. However, when prescribing a diuretic, they should also ensure that the drug used is prescribed at the appropriate therapeutic dosage level to enable patients to prevent the CV, thrombotic, and renal events that occur with long-term hypertension.

Introduction

Hypertension is a transformative condition in modern medicine due to the various numeric definitions of the disease, the decision of when to initiate therapy and to what level to treat, and the evolution of our understanding of the long-term complications of the hypertensive disease process. Hypertension is notable as 1 of the first conditions that only rarely manifested symptoms and whose eventual sequelae could take years, if not decades, to become known. In addition, hypertension was the first condition in which clinicians initiated therapy for patients who were otherwise healthy. Hypertension also led to 1 of the first screening programs for any disease as well as the first robust preventive effort for a chronic medical condition.¹

Clinical trials have been performed for 5 decades to evaluate the potential benefits of lowering blood pressure (BP) in patients with hypertension and its comorbid conditions (FIGURE 1).^2-37 The first clinical trial to identify the increased risk of cardiovascular (CV) mortality related to hypertension was published in the mid-1960s.^2,38 In fact, the Veterans Administration (VA) Cooperative trial was the first randomized, placebo-controlled, double-blind, multi-institutional drug efficacy trial ever conducted in CV medicine.³⁸ It involved 143 men who met the 1964 definition of hypertension (ie, diastolic BP [DBP] ≥115 mm Hg) and who were randomized to either triple therapy with low doses of hydrochlorothiazide (HCTZ), reserpine, and hydralazine, or to placebo. The trial was terminated early when, after 18 months of treatment, rates of morbidity and mortality were substantially lower in the treated group than in the placebo group.² The trial was the first to confirm that antihypertensive treatment, even in patients with existing CV damage and significant hypertension, could dramatically reduce the incidence of stroke, congestive heart failure (CHF), and progressive kidney damage.³⁸

FIGURE 1

Clinical trials in hypertension during the past 5 decades

The Medical Research Council trial of the treatment of mild hypertension (MRC-1) (ie, defined as DBP 90-109 mm Hg) demonstrated that a significant reduction in DBP among individuals receiving the diuretic bendroflumethiazide or the beta-blocker propranolol significantly reduced the rate of stroke compared with placebo, with a rate of 1.4 per 1000 patient-years of observation in the treatment group vs 2.6 per 1000 patient-years in the placebo group (P < .01).⁵ The treatment group also had significantly lower rates of all CV events than the placebo group, and this difference was statistically significant (P < .05). However, the treatment groups experienced significantly increased rates of adverse effects compared with placebo.⁵

Other early notable clinical trials that evaluated treatment options for hypertension in the general public include the Hypertension Detection and Follow-up Program (HDFP),³ the Hypertension Optimal Treatment (HOT) study,¹⁶ and the United Kingdom Prospective Diabetes Study/Hypertension in Diabetes (UKPDS/HDS).^17,18 The key outcomes of these trials are shown in TABLE 1.^{3,4,11,12,16,20,22,25,39,40}

TABLE 1

Findings from the early clinical trials in hypertension

Given that hypertension is far more common in older people who have increased rates of hypertensive target organ damage or CV disease (CVD), researchers have focused on the effects of antihypertensive therapy in this population for some time.⁴¹ Sentinel studies in this population include the European Working Party on High Blood Pressure in the Elderly (EWPHPE) study,⁴ the Medical Research Council trial of treatment of hypertension in older adults (MRC-2),¹² the Swedish Trial in Old Patients with Hypertension-2 (STOP-2),²² the Study on Cognition and Prognosis in the Elderly (SCOPE),²⁵ the Systolic Hypertension in the Elderly Program (SHEP) study,¹¹ the Systolic Hypertension in Europe (Syst-Eur) study,¹⁹ and the Systolic Hypertension in China (Syst-China) study.²⁰ The key outcomes of these trials are shown in TABLE 1. In general, these trials have shown that antihypertensive therapy has a marked benefit in a shorter period of time in older patients than in younger patients, particularly in terms of reduced stroke and CHF rates.

The Hypertension in the Very Elderly Trial (HYVET), which enrolled participants 80 years of age and older, demonstrated that reducing systolic BP (SBP) from 170 mm Hg to 145 mm Hg with indapamide sustained release 1.5 mg and perindopril 2 to 4 mg as needed reduced all-cause deaths 21% (P =.02), stroke-related deaths 39% (P =.05), and fatal and nonfatal heart failure (HF) 64% (P < .001), compared with placebo.⁴² The intervention group also experienced a 34% reduction in all CV events (P < .001) and a 30% reduction in stroke (P =.055).⁴² However, there is still no good evidence that reducing BP further in this population provides additional benefits over the concomitant risks.

In the 1980s, numerous trials were developed to address the question: “What is the best way to treat high BP?” These included the Heart Attack Primary Prevention in Hypertension (HAPPHY) trial,⁷ the Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) study,^8-10 the Treatment of Mild Hypertension Study (TOMHS),¹⁴ and the VA Cooperative Study on single drug therapy.¹⁵

Subsequently, several trials were conducted that focused on the safety of calcium antagonists for the primary or background treatment of hypertension. These included the International Nifedipine GITS Study of Intervention as a Goal in Hypertension Treatment (INSIGHT),²³ the Nordic Diltiazem (NORDIL) study,²⁴ the Australian National Blood Pressure Study 2 (ANBP2),²⁸ the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial,²⁶ the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial,²⁹ and the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) study.³⁷

These studies, conducted from the mid 1990s to the present, have shown that calcium antagonists, including amlodipine, diltiazem, nifedipine, and verapamil, are as effective as thiazide-type diuretics or beta-blockers in preventing CV events in patients with hypertension. Further, the LIFE trial demonstrated that the angiotensin II receptor blocker (ARB) losartan was more effective than the beta-blocker atenolol in reducing stroke events and that blockade of the renin- angiotensin system did not seem to affect CV outcomes in patients with HF with preserved systolic function, a common problem in patients with prolonged hypertension and left ventricular hypertrophy.²⁹

The largest randomized, double-blind, antihypertensive trial performed to date is the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). It involved 33,357 participants 55 years of age and older with hypertension and at least 1 other coronary heart disease (CHD) risk factor.²⁷ Participants were randomized to chlorthalidone, amlodipine, doxazosin, or lisinopril. The doxazosin arm was discontinued early because an increase in CV events was observed after 2 years, relative to the other treatment arms. At follow-up (mean, 4.9 years), there was no difference between the 3 groups in terms of the primary outcome (combined fatal CHD or nonfatal myocardial infarction [MI], analyzed by intent-to-treat) or all-cause mortality.²⁷ Of note, 5-year SBP levels were higher in the amlodipine (0.8 mm Hg, P=.03) and lisinopril (2 mm Hg, P < .001) groups than in the chlorthalidone group, whereas the 5-year DBP levels were significantly lower in the amlodipine group (0.8 mm Hg, P < .001).²⁷

Secondary analyses showed a higher 6-year rate of HF development in the amlodipine group than in the chlorthali-done group (10.2% vs 7.7%; relative risk [RR], 1.38; 95% con- fidence interval [CI], 1.25-1.52), whereas the lisinopril group had a higher 6-year rate of combined CVD (33.3% vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16), stroke (6.3% vs 5.6%; RR, 1.15; 95% CI, 1.02-1.30), and HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31) than the chlorthalidone group. The design of ALLHAT led to worsened control of BP in African Americans relative to white patients who were receiving lisinopril, which may have been an important factor in the subsequent increased rate of stroke in African American patients who were receiving lisinopril rather than chlorthalidone.²⁷

Subsequent to ALLHAT, the benefits and safety of calcium antagonists vs a thiazide diuretic combined with an angiotensin-converting enzyme inhibitor (ACEI) were ad-dressed by the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial.³³ This study randomized 11,506 patients with a mean BP of 145/80 mm Hg to combination therapy with benazepril (40 mg/d) and amlodipine (5-10 mg/d) or benazepril and HCTZ (12.5-25 mg/d). Other antihypertensive medications could be added to reach a target BP <140/90 mm Hg (130/80 mm Hg in patients with diabetes or renal insufficiency).³³ The study was stopped early at 3 years because the primary outcome of CV death, nonfatal MI or stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization occurred in 552 patients in the benazepril-amlodipine group compared with 679 patients in the benazepril-HCTZ group (9.6% vs 11.8%; RR ratio, 19.6%; hazard ratio [HR], 0.80; P < .001). The mechanism for the benefit observed in the benazepril-amlodipine group may relate in part to improved coronary blood flow that occurs with a calcium antagonist (compared with a diuretic) since BP control was virtually the same in both groups.

Another major hypertension study during the same era was the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).³² This study enrolled 19,257 patients in northern Europe with a mean age of 63 years, an untreated baseline BP ≥160/100 mm Hg or a treated mean BP ≥140/90 mm Hg, and 3 or more of 11 prespecified risk factors for CV. Patients were randomized to amlodipine, with or without perindopril, or atenolol, with or without a thiazide diuretic, and were titrated to reach a BP goal <140/90 mm Hg. The study was halted early after a mean follow up of 5.5 years. Although there was no statistically significant difference in the primary events of nonfatal MI plus fatal CHF between the 2 arms, fewer patients randomized to the amlodipine-based regimen experienced a fatal or nonfatal stroke (327 vs 422; HR, 0.77; 95% CI, 0.66-0.89; P=.0003) and total CV events and procedures were lower in patients taking the amlodipine-based regimen than in those taking the atenolol-based regimen (1362 vs 1602; HR, 0.84; 95% CI, 0.78-0.90; P < .0001).³² All-cause mortality was also lower in the amlodipine-based group (738 vs 820; HR, 0.89; 95% CI, 0.81-0.99; P=.025), and significantly fewer patients in this arm developed diabetes (567 vs 799; HR, 0.70; 95% CI, 0.63-0.78; P < .0001).³²

Patients with diabetes in ASCOT who were titrated to achieve a target BP <130/80 mm Hg experienced significantly lower mortality and stroke when taking the amlodipine-based regimen than when taking the atenolol-based regimen (HR, 0.86; 95% CI, 0.76-0.98; P=.026).³² In the group taking the atenolol-based regimen, fatal and nonfatal strokes were reduced by 25% (P=.017), peripheral arterial disease by 48% (P=.004), and peripheral revascularization procedures by 57% (P < .001). There were no statistically significant differences in the endpoints of CHD deaths and nonfatal MI in the diabetes subgroup.

Combination therapy and guideline recommendations

By the 1970s, it became clear that combinations of antihypertensive drugs increased BP lowering efficacy through both additive and synergistic mechanisms. These combinations also reduced adverse events because lower doses of each drug could be used, whereas drugs from different classes might offset each other’s adverse effects. In addition, combining antihypertensive drugs could prolong duration of action, possibly providing additional target organ protection.⁴³ Combining drugs from complementary classes has also been shown to increase the likelihood of BP lowering compared with increasing the dose of a single drug, thus reducing the time required to reach BP goal.^31,44-46

The 2010 American Society of Hypertension (ASH) position statement on combination therapy in hypertension therapy notes that at least 75% of patients will require combination therapy to reach goal.⁴⁷ In addition, a meta-analysis of 9 randomized clinical trials found that combination treatment using a thiazide or thiazide-like diuretic as one of the components could provide a significantly greater effect than monotherapy lacking the diuretic, with similar discontinuation rates.⁴⁸

Government guidelines in the United States, now nearly 10 years old, do not recommend combination therapy as a first-line approach unless patients have stage 2 hypertension (SBP ≥160 mm Hg or DBP ≥100 mm Hg). At that point, the guidelines recommend combination therapy with a thiazide or thiazide-type diuretic plus either an ACEI, ARB, beta-blocker, or calcium antagonist.⁴⁹ More-specific recommendations are provided for patients with compelling indications (eg, HF, ischemic heart disease, chronic kidney disease, recurrent stroke, diabetes, and high coronary disease risk), as shown in TABLE 2.^41,49 New recommendations from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) are expected later this year.

TABLE 2

Antihypertensive treatment in patients with compelling indications^41,49

Indication	Diuretic	BB	ACEI	ARB	Calcium antagonist	Aldosterone antagonist
Heart failure
Post MI
CVD or high CVD risk
Anginaa
Aortopathy/aortic aneurysma
Diabetes
Recurrent stroke prevention
CKDb
Early dementiaa
= ACCF/AHA recommendation; = JNC-7 Express recommendation. ACCF, American College of Cardiology Foundation; ACEI, angiotensin-converting enzyme inhibitor; AHA, American Heart Association; ARB, angiotensin-receptor blocker; BB, beta-blocker; CVD, cardiovascular disease; CKD, chronic kidney disease; MI, myocardial infarction. aNot considered “compelling” indication in JNC-7 Express guidelines. bNot considered “compelling” recommendation in ACCF/AHA recommendations. Source: Journal of the American College of Cardiology by American College of Cardiology. Reproduced with permission of Elsevier Inc. in the format Journal via Copyright Clearance Center.

Recent guidelines from ASH describe combination therapies of hypertension in categories of preferred, acceptable, and less effective, based on efficacy in lowering BP, safety and tolerability, and certain known outcomes from longer-term trials (TABLE 3).⁴⁷

TABLE 3

Drug combinations in hypertension: Recommendations from the American Society of Hypertension⁴⁷

In 2010, the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) published an expert consensus document on hypertension in the elderly. It recommends single therapy or combination therapy with an ACEI, ARB, calcium antagonist, or diuretic for patients 65 years of age and older with stage 1 hypertension and no “compelling” indications (eg, HF, post-MI, known coronary disease, angina, aortopathy/aortic aneurysm, diabetes, recurrent stroke prevention, chronic kidney disease, and early vascular dementia), but combination therapy for those with stage 2 hypertension and no compelling indications. For the former group, the panel notes that the combination of amlodipine with a renin-angiotensin aldosterone system blocker may be preferable to a diuretic combination, although either is acceptable.⁴¹

For patients with compelling indications, the ACCF/AHA panel recommends condition-based combination therapy with 2 or more of the therapies summarized in TABLE 2.^41,49 The panel’s algorithm for the management of hypertension in the elderly is depicted in FIGURE 2.⁴¹

FIGURE 2

ACCF/AHA algorithm for the management of hypertension in the elderly⁴¹

In contrast, patients 55 years and older, or blacks of African or Caribbean origin of any age, should begin treatment with a calcium channel blocker (CCB).⁵⁰ If they cannot tolerate a CCB, or for those with HF (or at high risk of HF), the guidelines recommend beginning therapy with a diuretic (preferably chlorthalidone or in-dapamide unless the patient’s hypertension is already controlled with bendroflumethiazide or HCTZ).

If initial treatment fails to lower BP adequately, step 2 of the NICE guidelines for all populations is treatment with an ACEI or ARB in combination with a calcium antagonist.⁵⁰ If further therapy is necessary (step 3), a thiazide diuretic (or thiazide-like) should be added to that combination. It is also recommended that patients with drug-resistant hypertension (ie, taking 3 agents at maximally tolerated doses, 1 of which should be a diuretic) should receive additional treatment with low-dose spironolactone (if their serum potassium level is ≤4.5 mmol/L) and higher-dose thiazide-type diuretics (if their serum potassium level is >4.5 mmol/L). If the diuretic is not tolerated or is ineffective, an alpha- or beta-blocker may be added. If patients continue to exhibit continued resistance, NICE recommends referral to a hypertension specialist. The NICE algorithm for the treatment of hypertension is shown in FIGURE 3.⁵⁰

FIGURE 3

NICE algorithm for treatment of hypertension⁵⁰

Conclusion

With 7 major classes of antihypertensive drugs and several drugs within each class, there are numerous combinations available to clinicians to manage hypertension. Existing clinical trials cannot possibly evaluate all possible combinations. Yet, as noted in the ASH statement on combination therapy, the importance of achieving goal BP in individual patients cannot be overemphasized because small differences in on-treatment BP translate into major differences in the rates of CV events.⁴⁷ When considering appropriate and effective antihypertensive therapies, clinicians should assess the evidence presented in this article and from the various clinical guidelines cited. Each patient is unique and it is important for clinicians to identify the most-effective treatment regimen for each individual patient.