Fixed‐Dose Combination Therapy—Is It Time for This Approach to Hypertension and Dyslipidemia Management?

To date, therapy for most cardiovascular disorders has applied the principle of one drug for one risk factor. This is a treatment approach that has been reluctantly accepted due to lack of a suitable combination therapy alternative. Now, two combination products are available that will simplify the process of simultaneous risk‐factor management. The first of these is a pravastatin and aspirin combination and the second is a combination of amlodipine and atorvastatin. The latter is a conceptually innovative therapeutic option.

Approximately 30 million Americans have hypertension and dyslipidemia and the current rather disappointing 10% success rate for the simultaneous control of these disorders argues for alternative treatment strategies such as this fixed combination of an antihypertensive agent and a lipid‐lowering agent. Time will tell how many physicians and/or patients embrace this therapeutic approach. Future combinations will expand the treatment options and will likely employ other antihypertensive drug classes, such as angiotensin‐converting enzyme inhibitors and angiotensin‐receptor blockers, with various other lipid‐reducing agents. These new combination products could pave the way for more expansive combinations—like the recently proposed polypill.

PERSPECTIVE

Unlike fixed‐dose combination antihypertensive therapy, which was ushered in when two diuretic‐containing combinations (reserpine‐hydralazine‐hydrochlorothiazide and α‐methyldopa‐hydrochlorothiazide) became available in 1961, there is no history of fixed‐combination antihypertension/dyslipidemia therapy. ¹ The amlodipine/atorvastatin product (Caduet; Pfizer Inc., New York, NY) will break the ice.

This concept is a considerable departure from the traditional combination‐product therapy that has been employed in the treatment of hypertension.

RATIONALE

Hypertension and dyslipidemia are conditions that coexist on a regular basis. In a recent study utilizing data from the third National Health and Nutrition Examination Survey (NHANES III), it was estimated that almost 15% of US adults (representing approximately 30 million persons) have both hypertension and dyslipidemia. ² It was also shown that more than 60% of patients with hypertension also have dyslipidemia; conversely, approximately 50% of patients with dyslipidemia have hypertension. ² Hypertension and hypercholesterolemia are the two leading risk factors for heart disease, which is the leading cause of death worldwide, and these two disturbances together cause an increase in coronary heart disease‐related events that is more than simply additive for anticipated event rates with each disease. ³

There appears not to have been a specific rationale for the combination of amlodipine and atorvastatin beyond that of reducing blood pressure (BP) and cholesterol levels simultaneously with the presumed attendant benefits. Thus, unlike angiotensin‐converting enzyme inhibitor or angiotensin‐receptor blocker therapy—where there is a presumption of end organ protection in excess of what might be anticipated from BP reduction alone—with the dihydropyridine calcium channel blocker amlodipine the major end organ protection benefit seems to be mainly BP driven. ⁴ , ⁵ However, it has been shown that the effect of the combination of amlodipine and atorvastatin on small and large artery compliance is additive and may even be synergistic, implying that such a combination has a beneficial effect on some surrogate markers. ⁶ To what degree statins reduce BP and what might be the best interacting antihypertensive agent is currently speculation. ⁷ This question is being asked in the Anglo‐Scandinavian Cardiac Outcomes Trial (ASCOT), but is unanswerable based on the currently available ASCOT data. ⁸

OPINION

Academic opinion on this type of combination product for the simultaneous treatment of hypertension and dyslipidemia is yet to be fashioned. No doubt it will be sharply divided. However, it is likely that the ease of use of such a combination will rapidly attract supporters. It is not unreasonable to suppose that the marketing of this combination will provide for prompt use by many physicians, although its very recent availability means that it is not included in the treatment guidelines and the management algorithms that in many instances may have already individually positioned calcium channel blocker (as an antihypertensive) ⁹ and statin (as a cholesterol‐lowering agent) therapy. ¹⁰

ADVANTAGES

The objective of fixed‐dose combination antihypertensive/dyslipidemia therapy is to procure better BP and lipid control and to do so in a cost‐effective fashion. Some debate exists as to the optimal approach to cholesterol lowering, with data supporting a treat‐to‐target method ⁸ or a fire‐and‐forget tactic. ¹¹ The availability of a fixed‐combination antihypertensive/dyslipidemia product supports the latter line of attack. An additional consideration in the management of these disorders is that their long‐term control is often coupled with the ease with which normalization occurs once a decision has been made to initiate pharmacologic therapy. Although cited as a factor that may favor fixed‐dose combination therapy, it is not intended to trivialize what is often a complex interactive therapeutic process. In a patient with hypertension and dyslipidemia, this phenomenon involves response modification to innumerable environmental stimuli and the acquisition of new mannerisms and/or behavior patterns that support reliable pill taking.

DISADVANTAGES

A disadvantage to fixed‐dose antihypertensive combination products is a lack of dosing flexibility for its individual components. However, this will not be the case with the fixed combination of amlodipine and atorvastatin because several dosage strengths (dose range 5–10 mg amlodipine and 10–80 mg atorvastatin) will be available. In addition, fixed‐dose combination antihypertensive/dyslipidemic therapy may not provide adequate drug amounts to manage illnesses such as angina (if a dose higher than 10 mg amlodipine is necessary) that can coexist with hypertension.

PHARMACOLOGY

The role of pharmacokinetics and pharmacodynamics in response to fixed‐dose antihypertensive/dyslipidemic combination products is a work in progress. The pharmacodynamic contribution of the individual components of this fixed‐dose combination product to response is hard to determine from the available literature. This is a complex area with individual patient sensitivity determining the response. The pharmacologic nuances of both amlodipine and atorvastatin apply to the combination product. Absorption of this combination does not appear to have a food‐effect ¹² and it is bioequivalent ¹³ to its components when individually administered.

CLINICAL RESULTS

The case for fixed‐dose combination antihypertensive and dyslipidemic therapy can be argued most vigorously in the context of the current control rate, which is approximately 10% for both disturbances jointly treated. US Food and Drug Administration approval of the amlodipine/atorvastatin product Caduet (Pfizer, New York, NY) was based on a double‐blind, placebo‐controlled study enrolling 1660 subjects with the comorbid conditions of hypertension and dyslipidemia. Results showed that all combination‐treatment groups of amlodipine and atorvastatin demonstrated statistically significant dose‐related reductions in systolic and diastolic BP as well as low‐density lipoprotein cholesterol compared with placebo. Subjects received once daily treatment with eight dose combinations of amlodipine and atorvastatin (5/10 mg, 10/10 mg, 5/20 mg 10/20 mg, 5/40 mg, 10/40 mg, 5/80 mg, or 10/80 mg), amlodipine alone (5 mg or 10 mg), atorvastatin alone (10 mg, 20 mg, 40 mg, or 80 mg) or placebo.

TOLERABILITY

Amlodipine/atorvastatin will be available in multiple combination strengths. Whereas compound‐specific side effects can be limited by supporting physiologic actions of one or the other of the components in the instance of fixed‐dose combination antihypertensive therapy, no such benefit derives from combining atorvastatin with amlodipine or the reverse. Thus, issues of liver enzyme changes and/or muscle damage with atorvastatin and vasodilator side effects with amlodipine should occur with a similar frequency to what would be observed if either drug was individually administered.

COMPLIANCE

Detailed management guidelines for the treatment of hypertension and hyperlipidemia have now been disseminated worldwide. Despite the prompting of such groups as the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) the World Health Organization, and the International Society of Hypertension, as well as the recommendations of the National Cholesterol Education Program Adult Treatment Panel III, ⁹ many physicians still hesitate to strictly adhere to what are solid evidence‐based recommendations. ¹⁴ For example, a recent survey found that 41% of physicians had not heard of or were not familiar with the JNC VI guidelines. ¹⁵ A similar prescription malaise exists for the treatment of dyslipidemia. Thus, a significant gap still exists between desired control rates for hypertension/dyslipidemia and what is currently achieved in clinical practice.

A number of factors can be implicated in the failure of current therapeutic regimens to reduce BP in a more significant proportion of the population, with disease state identification and medication compliance being of the utmost importance. ¹⁶ Despite decades of attention to noncompliance to treatment for hypertension and more recently for dyslipidemia, the problem remains a significant factor in the inadequate control of these disease states. Current approaches to enhance compliance use patient demographics, medication characteristics, clinical factors, health beliefs, and the quality of patient‐provider communication. Decreasing the total number of daily doses needed for joint BP and lipid control represents a major advantage of fixed‐dose combinations. Thus, the use of once daily fixed‐dose antihypertensive/dyslipidemic combinations can be expected to enhance medication compliance. However, if the antihypertensive component of this fixed‐dose combination must be given twice daily, such supplemental dosing may reduce the previous gain in compliance.

PRESCRIPTION STRATEGY

Single‐drug therapy remains the preferred way to begin treatment of hypertension and/or dyslipidemia, although in many cases neither stratagem is able to bring BP or lipid status to goal for a sustained period of time. The options for multi‐drug therapy are quite simple: either fixed‐dose combination therapy or multiple drugs added sequentially one to another to arrive at an effective regimen. Advocates will no doubt exist for both approaches. A serviceable approach is to prescribe two or more drugs sequentially with appropriate dose titration of each; once BP and cholesterol control is accomplished, an appropriate fixed‐dose combination can be substituted. Alternatively, if at the start of therapy, multidrug treatment is believed necessary and compliance is a relevant concern, a fixed‐dose combination product can be considered. Currently, when this fixed‐dose combination product is deemed to be first‐step therapy, the recommended starting dose should be based on the individual recommendations for starting doses for the monotherapies.

REGULATORY CONSIDERATIONS

Why more fixed‐dose antihypertensive combinations are not approved for first‐step treatment in the United States relates to the regulatory position adopted by the US Food and Drug Administration. The regulation states that two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects. The dosage of each component should be such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug. The inherent excess risk of adverse effects caused by addition of a second (or third) drug must be balanced by greater efficacy. The latter issue has proven a sticking point and is why these drugs are not more widely recommended as first‐step therapy. This regulatory conundrum has been sidestepped for the moment (and probably rightfully so) because there are considerable conceptual dissimilarities between the amlodipine/atorvastatin fixed‐dose combination and fixed‐dose antihypertensive medications.

CONCLUSIONS

The launch of this combination amlodipine/atorvastatin product will open the floodgates to development and release of other cross‐risk‐factor, single‐pill combinations. Whether this strategy will improve outcome awaits confirmation.