Support for Combined Administration of Antihypertensive and Lipid-lowering Agents to Reduce Cardiovascular Events—The Emergence of the Multipill

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About 26% of the adult population worldwide has hypertension. In the US adult population, about 30% have hypercholesterolemia and 50–75%, depending on age range, share both. In addition, hypertension and hypercholesterolemia frequently coexist with diabetes, chronic kidney disease, cigarette smoking, obesity and sedentary lifestyle, all of which are potent risk factors for cardiovascular diseases, the most common cause of death in adults in the industrialized world. Traditional treatment approaches targeted each modifiable risk factor as an isolated event. At least two observations led to adjustments in this approach. First, the aim of treatment is to reduce cardiovascular events rather than to achieve a level for a particular risk factor. Second, and more importantly, clinical trials such as the Heart Protection Study, the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) and others show that prominent reductions in cardiovascular events, including stroke, occur in patients with moderate to high cardiovascular risk profiles when blood pressure lowering and cholesterol lowering medications are combined, in the absence of a primary indication for both. In these patients, the emerging therapeutic paradigm is to treat the overall level of cardiovascular risk rather than the level of a particular risk factor. The logical extension of this is a single pill aimed at more than one cardiovascular risk.

The first major product to be marketed with this in mind is a combination of amlodipine, a potent antihypertensive, and atorvastatin, a potent cholesterol-lowering agent. At this stage it is not clear if the combined effects are synergistic, but they are at least additive.Additional benefits may arise from reduced cost and improved patient acceptance from simplification.

When Two Is Not Better Than One

From a practical perspective, the biggest problem with the traditional approach was the need for multiple medications, raising spectres of patient compliance and expense. Anything that can truncate costs and improve adherence to daily medications should contribute to the efficacy of the individual medications.

Ideally, all medications that a person needs to take simultaneously would be merged into a single pill. The practical reality of creating such a pill, however, is that you cannot simply 'glue' all the individual agents together; there are technical limitations to overcome. The agents must:

  • be pharmacokinetically compatible;
  • be able to be taken at the same time in the same fasting or non-fasting states;
  • have comparable durations of action and independent metabolic clearances;
  • not interfere with the other's bioavailability—absorption in the gastrointestinal tract, or hepatic and renal clearance;
  • have acceptable compound pill size; and
  • have comparable shelf-life stability.

Once you overcome these technical problems then you have to demonstrate that the clinical efficacy of the combined pill is at least equal to the agents singly, and that there is no increase in the side effects or adverse drug effects.This is a lot of work.

For a multipill to be clinically acceptable, the other characteristic that is good to see in compounded agents such as Pfizer's Caduet is that the individual agents have distinct side effects. If you give a patient a multipill and they come back with a headache that they link to the initiation of that drug, that is rather non-specific and there is no choice but to reduce the combined medications. However, if they come back and say that they have developed ankle edema, because that is so typical of amlodipine I can reduce the proportion of that drug only. Or if they develop muscle aches that are such a characteristic side effect of statins, then I can reduce the statin component. It is good to be able to manage the individual components more or less independently, so it is essential that they have compatible pharmacokinetic properties but it is also handy if they have distinct side effect profiles so we can distinguish them if patients come back with complaints. Additionally, the most common combination of individual medication strengths needs to be available.

This concept of combining many different treatments into one pill is not new. There is a solid history of compounding various agents such as a beta-blocker and a diuretic for hypertension or various antibiotics to treat an infection. However, combining a hypertensive treatment to regulate blood pressure with a statin for cholesterol-specifically two agents that are apparently for two disease processes-has not been done before. Therefore Caduet, combining its proprietary atorvastatin and amlodipine drugs is, to my knowledge, the only multipill in the cardiovascular (or any other) realm that is aimed at two independent risk factors.

Clinical Trial Proof

It is, of course, vital to have proof that the strategy of combining lipid-lowering treatment with blood pressure reduction has clinical benefit. To date there have been two studies that took a hypertensive population not otherwise indicated for primary dyslipidemia and randomized them to receive a lipid-lowering therapy as well.

The US study was ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) and the European study was ASCOT. ALLHAT was the largest hypertensive trial ever conducted with more than 42,000 patients.

There were a few differences between ALLHAT and ASCOT. The first was that in the US study, those patients eligible for lipid-lowering therapy were randomized to receive either a statin (pravastatin) or usual standard of care. The results of that study were disappointing; randomization to the pravastatin arm achieved no benefit. ALLHAT was followed soon after by ASCOT, which was similar except it took patients with hypertension who had acceptable cholesterol values and randomized them to placebo or atorvastatin 10mg. That study showed early and dramatic benefits of the addition of atorvastatin to either of two antihypertensive strategies.

So ASCOT is the primary clinical trial that demonstrates that the reduction of total cholesterol and specifically low-density lipoprotein (LDL) cholesterol to lower-than-usual levels in a hypertensive population at moderate cardiovascular risk achieves benefits in terms of reduction of fatal and non-fatal myocardial infarction and stroke. There have been other similar trials where the mix was flipped, where patients who had coronary artery disease and were on statins were treated with an antihypertensive even though their blood pressure was 'normal' to see if there was any benefit. The most notable of these was the CAMELOT (Comparison of AMlodipine vs Enalapril to Limit Occurrences of Thrombosis) study that showed benefits of adding amlodipine to patients with coronary artery disease who were already on standard treatment for that.

Improving Adherence

Caduet is available in all permutations that you would use clinically: amlodipine, 5-10mg a day; atorvastatin, 10-80mg per day. While theoretically a patient on both medications should not experience any new side effects after being moved onto Caduet, the reality is—anecdotally—that they may. This is probably explained by improved adherence. Patients who were on the separate doses of amlodipine and atorvastatin and then who, upon conversion to Caduet, come back complaining of, for example, ankle edema,may in fact have tended in the past to be more adherent to one medication than the other.

There are other data on compliance, but they are relatively soft. As expected they show extended duration of taking medicines. In general there is a horrible attrition rate in patients taking statins—within six months fewer than 50% are still taking them. You can extend that by either using a single pill or one that is linked to a higher degree of patient education than if it were doled out independently. If a patient feels that their best interests are dually served by taking a medicine, one could argue that they are twice as likely to take it than single agents. In contrast, there is certainly no evidence that there is diminished compliance.

As well as adherence, the dual pill is less costly. Assessing—at least in the US environment—the cost to the patient is difficult with the various prescription plans, but it has been at least borne out that whether medication is provided from a central pharmacy nationally or commercially, that the cost of providing the two agents is less when they are co-compounded than when they are individually distributed. That makes logistical sense from packaging alone.

On the Beat

It is very difficult to convince patients to take a daily medication—even for a potentially fatal condition—for which they do not see the immediate benefit. For the future of medications for conditions such as cardiovascular disease it would be very nice if you could take a pill once a month, such as people do now for osteoporosis. Anything that improves patient adherence in the long term will lead to additional benefits in terms of cardiovascular event reduction. We now have plenty of weaponry for cardiovascular risk reduction and it is not the potency of the weapons but the long-term acceptance of our patients to follow through with this medication that frequently diminishes our success.