Heart disease is the leading cause of death in the United States and hypertension is an important risk factor for cardiovascular (CV) disease. Affecting up to 30% of the population, when hypertension is well controlled it reduces the risk of CV events and death. The importance of lowering blood pressure (BP) to reduce CV outcomes is known. BP reduction to levels well below 140/90 mm Hg reduces the risk of heart failure by more than 50%, stroke by 35% to 40%, and myocardial infarction (MI) by 20% to 25%.
All international guidelines recommend that BP be reduced to lower than 140/90 mm Hg to decrease the risk of CV events. The most recent Expert Panel Report known as the Joint National Committee (JNC 8) guidelines recommend a goal BP of less than 150/90 mm Hg in those over the age of 60 and less than 140/90 mm Hg in those younger than 60 years, those with diabetes, and/or chronic kidney disease (CKD). Currently only 53% of people with hypertension would meet these criteria based on a target of less than 140/90 mm Hg; based on more recent trial results, if adopted, would make this percentage smaller. The newly published Systolic Blood Pressure Intervention Trial (SPRINT), with more than one-third of the patients being over age 60 years, with 28% being over age 75 years, demonstrated a substantial reduction in heart failure as well as all-cause mortality among those randomized to a BP below 120 mm Hg systolic, using an automated oscillometric device. These patients did not have a history of prior strokes or diabetes.
Given the difficulty in achieving BP goal with one medication, even under controlled conditions in clinical trials where two or more medications are required in more than 50%, the use of single pill combinations in the general population are mandatory ( Fig. 27.1 ). The concept of initial combination therapy is not new because one of the first large clinical trials published in the late 1960s, the Veteran Affairs Cooperative Study, showed reduced morbidity with improved BP control using triple therapy combinations.
Rationale for Initial Combination Therapy
History
The use of combination therapies started in the 1950s, when pills containing reserpine were introduced. This was then followed by availability of several other formulations in the 1960s and 1970s that contained thiazide diuretics, including the triple combination pill of hydralazine and hydrochlorothiazide and reserpine, as well as in combination with potassium-sparing diuretics, beta-blockers, and clonidine. In the 1980s, thiazides were combined with angiotensin-converting enzyme (ACE) inhibitors and in the 1990s, a combination of an ACE inhibitor and calcium channel blocker (CCB) was approved ( Fig. 27.2 ). Although combination BP lowering therapy was available and proven to reduce BP and mortality in clinical trials, the control of BP with stepwise management was advocated by early guidelines.
The first report favoring combination therapy as an initial approach was seen in 1997 by the JNC VI panel. Since this report, it is clear that initial use of single pill combination therapy is superior to a stepwise approach in controlling hypertension, with 12% more patients at their target BP. Moreover, use of combination therapy improves BP control with fewer adverse events compared with doubling the dose of a single pill. Addition of an antihypertensive agent from a different class is five times more effective in improving BP control than doubling the dose of a single drug ( Fig. 27.3 ). Improvement in BP control occurs when even half the dose of the individual drugs are used in a combination pill compared with full doses of each as monotherapy.
Philosophy and Physiology of Combination Therapy
There are several reasons why BP medications used in combination would allow better management of hypertension. First, there are multiple systems that regulate BP and include sympathetic nervous system (SNS), renin-angiotensin system (RAS), and volume modulators from the kidney and heart like natriuretic peptides. It is difficult to determine with certainty which system is dominant in a particular patient and the use of different classes of medications will increase the chance of controlling BP faster and more effectively. Moreover, an increase dose of a single agent is less likely to achieve BP control than adding lower doses of a second agent.
Another reason for using combination therapy is to offset the body’s counter-regulatory mechanisms to a particular agent, that is, diuretics used alone can result in relative volume depletion and activate the RAS and to a lesser extent the SNS. The use of agents that block these systems, such as ACE inhibitors or beta-blockers, counteract the body’s response to diuretics and are complementary to diuretic action to low BP. The use of vasodilators such as hydralazine and minoxidil cause a counter-regulatory activation of the RAS and SNS as well as increase sodium retention. Hence, they are mandated to be used with a beta-blocker and diuretic, making the use of antagonists of these systems additive.
Medication Adherence
There are many reasons that only about 50% of hypertensive patients have BP at goal despite the availability of multiple therapies. Two of the most prominent are poor adherence to medication regimens by the patient and therapeutic inertia by physicians.
Medication adherence is a major issue in managing hypertension. Urine screening for medications and their metabolites in those considered to have resistant hypertension, taking approximately six medications a day, showed that about 53% were not adherent to therapy. Of these, 30% were completely nonadherent and 70% were partially adherent, with 82% of the latter taking less than 50% of their prescribed regimen. This was not dependent on the type of antihypertensive medication.
The evidence for initial use of antihypertensive single pill combinations on outcomes is clear. In addition to the older VA studies already mentioned, the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial is the most recent CV mortality trial randomizing to two different single pill BP lowering combinations. In this trial, 32% required another drug in addition to the initially randomized single pill dual combination therapy. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study demonstrated that almost half the patients were on multiple medications by five years. In the International Verapamil-Trandolapril Study (INVEST), the majority (>80%) of the patients required two or more medications to reach goal and in the African American Study of Kidney Disease and Hypertension (AASK) study, an average of three or more antihypertensive agents were needed for the tight BP control group requiring a mean arterial pressure of less than 92 mm Hg ( Fig. 27.1 ).
It is obvious that single pill combination therapy improves adherence by reducing the absolute number of pills and their frequency. The more frequently a medication needs to be taken the lower the probability it is taken, with adherence also dropping from 77% to 55% if four drugs are taken as compared with one. Even when the same two drugs are given as individual pills, adherence rates with combination therapy are significantly higher ( Fig. 27.4 ) and can reduce nonadherence by up to 24%.
Therapeutic Inertia
Therapeutic inertia, or physician inaction in the face of a BP that is above target, is another major reason why hypertension remains poorly controlled. More than 7200 patients studied demonstrated that physicians only made medication changes in 13.1% of visits where BP was above guideline goal, although more recent studies show this has been improving. This inaction by physicians is known to have a significant effect on the degree of BP control and accounts for almost 20% of variance in control. It is projected that if medication changes were made in 30% of visits, the proportion of patients reaching BP target would rise from 45.1% to 65.9%. One of the major reasons physician inertia is a problem, is physicians’ perception that an uncontrolled patient is actually at target goal.
Adverse Side Effects
Paradoxically, one of the major reasons taught to avoid combination medications is potential for adverse events. This is antithetical to all published data. All single pill combinations available and approved by the United States Food and Drug Administration (FDA) have demonstrated added BP lowering efficacy with fewer adverse events compared with individual higher dosed components of the combination. Examples of combinations that avoid adverse events include a thiazide diuretic with a potassium-sparing diuretic to avoid hypokalemia. ACE inhibitors induce vasodilation that reduces the incidence of peripheral edema caused by arterial vasodilation of CCBs. Likewise, RAS blockers become more efficacious for BP lowering when used with thiazide-like diuretics and hence, many such combinations exist. Tolerability also improves as combination therapy allows use of lower doses of the individual medications, and using a half standard dose of a drug will only reduce its BP lowering efficacy by 20% but will also reduce the risk of adverse events.
Available Single Pill Combinations
As discussed, there is a key rationale for combining certain classes of antihypertensive agents to reduce BP ( Fig. 27.5 ). Multiple single pill combinations of antihypertensive medications are approved by the FDA and other authorities around the world ( Table 27.1 ).
| Preferred | ACE inhibitor/diuretic a ARB/diuretic a ACE inhibitor/CCB a ARB/CCB a |
| Acceptable | Beta-blocker/diuretic a CCB (dihydropyridine)/β-blocker CCB/diuretic Renin inhibitor/diuretic a Renin inhibitor/ARB a Thiazide diuretics/K+ sparing diuretics a |
| Less Effective | ACE inhibitor/ARB ACE inhibitor/β-blocker ARB/β-blocker CCB (nondihydropyridine)/β-blocker Centrally acting agent/β-blocker |
Renin-Angiotensin System Blockers With Calcium Channel Blockers
Single pill combinations of CCB with RAS blockers such as ACE inhibitors, angiotensin receptor blockers (ARBs), and direct renin inhibitors have been studied. Combinations of RAS blockers with either thiazide diuretics or CCBs are preferred therapy according to the American Society of Hypertension Consensus Panel Report, given that such combinations reduce mortality with fewer adverse events.
RAS blockers reduce the CCB-induced activation of the RAS and SNS systems that are caused by vasodilatory effect of CCBs. With the activation of the RAS system by CCBs, the antihypertensive effect of RAS blockers is amplified. The use of ACE inhibitors also reduce peripheral edema caused by CCBs and, when used in combination with a nondihydropyridine CCB (i.e., diltiazem or verapamil), there is a synergistic effect on albuminuria reduction.
The combination of ACE inhibitors and CCBs has been established to be superior in reducing BP as compared with its individual monotherapies. The ACCOMPLISH trial was the first trial to study two different single pill combinations on CV and renal outcome. The ACE inhibitor (benazepril) was used in combination with a CCB (amlodipine) or hydrochlorothiazide (thiazide diuretic) in hypertensive patients at high CV risk. Despite similar attained BPs, the trial was terminated early because of a large difference in the primary endpoint of CV events favoring the ACE inhibitor/CCB combination (9.6% versus 11.8%, respectively). Further study showed that patients with known coronary artery disease at baseline also had significantly reduced CV events on the ACE inhibitor/CCB combination.
The effect of these combinations on CKD progression, a prespecified secondary endpoint in ACCOMPLISH, demonstrated fewer CKD events (doubling of creatinine or end-stage renal disease) with a slower decline in estimated glomerular filtration rate (eGFR) in the benazepril/amlodipine group.
Many trials have assessed BP lowering ability of various combinations and all have shown additive benefit. The ARB (valsartan) and a CCB (amlodipine) have been studied. Various doses of amlodipine plus valsartan were compared with monotherapy and placebo in those with diastolic BP of 95 to 110 mm Hg. Use of the combination pill resulted in greater reduction of both systolic and diastolic pressures over the monotherapy. The incidence of edema was lower in those on combination therapy.
The combination of aliskiren with the CCB amlodipine has also been compared with the individual component monotherapies. The combination group had significantly lower BPs even when used at half doses ; however, other studies have shown that the half-dose combination therapy is equivalent to full dose amlodipine.
Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers with Diuretics
The additive BP lowering effects of an ACE inhibitor or ARB with a thiazide diuretic are well known. The efficacy of the combination comes from their complimentary mechanisms of action because the use of a diuretic activates the RAS system by causing intravascular volume depletion. The combination with RAS blockade is also useful because it reduces the risk of hypokalemia as an adverse effect of thiazide.
Multiple trials have shown a significantly greater BP reduction in those on combination ACE inhibitors or ARBs with a thiazide or thiazide-like diuretic (chlorthalidone or indapamide) as compared with monotherapy. Several outcome studies also show the benefits of these combinations, which include the perindopril protection against recurrent stroke study (PROGRESS). A perindopril-based antihypertensive treatment was compared with placebo in those who have had a history of stroke or transient ischemic attack, with the ACE inhibitor added to indapamide if strict BP control was needed. The ACE inhibitor/diuretic group was compared with placebo to determine the effect on fatal and nonfatal stroke. The trial revealed a reduced incidence of stroke in the combination group compared with placebo (10% versus 14%, respectively), whereas monotherapy with perindopril was not different from placebo.
In the Hypertension in the Very Elderly Trial (HYVET), patients 80 years old and older were randomized to BP control of less than 150/80 mm Hg using indapamide, with the addition of perindopril if needed, to assess the effect on fatal and nonfatal stroke. The trial was stopped early because of a large difference in outcome between the two groups favoring the treatment group. It is worth noting that this trial also showed that the majority of the groups required more than two medications to reach goal.
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