Use of Combination Therapies

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.

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.