Is it time to reconsider long-term use of four large classes of cardiovascular drugs?

In a review article recently published in the Journal of the American College of Cardiology, the authors address this very question.

The authors focus their review on the “big four” types of medications used (often in combination) to treat coronary heart disease: aspirin, beta-blockers, statins and ACE inhibitors. Millions of patients with coronary heart disease are often kept on some combination of these medications for decades.

Though evidence abounds for the benefit of these drugs in the first few years after a coronary event, the authors contend there is “inadequate evidence” that these benefits continue past this time.

“Therefore, we feel it is important to challenge the assumption that the efficacy and safety of drugs given in the relatively short term remain the same over the long term and into old age,” authors Xavier Rossello, MD; Stuart Pocock, PhD; and Desmond G. Julian, MD write.

Limitations of Randomized Clinical Trials

Randomized clinical trials (RCTs) are often called the “gold standard” of the research world, and are the basis for the U.S. Food and Drug Administration’s approval of drugs for market use. The authors express concern, however, that the trials that brought the “big four” to market may not be enough to justify long-term use, especially in the elderly.

For one, the RCTs in question often did not follow patients on these medications for longer than a few years. An extreme example of this is a meta-analysis the authors cite that found that the average follow-up period across 82 RCTs was 1.4 years. The authors comment on this limitation of RCTs: “In principle, we need RCTs of post-MI medications to be extended into truly long-term follow-up. However, in practice, to achieve trials with >5 years follow-up is a major challenge.”

Another issue the authors raise is the average age of study populations in cardiovascular RCTs. The elderly are often poorly represented, and sometimes excluded, from RCT populations, making the true effectiveness of long-term cardiovascular medication use in this population difficult to know for certain.

For example, the authors report that elderly patients aged 75 and older account for 36 percent of all heart attacks in routine practice. But among patients enrolled in acute coronary syndrome clinical trials between 1966 and 2000, only 7 percent were 75 or older.

Deprescribing

The authors also touch on the concept of “deprescribing,” or withdrawing medications from a patient’s regimen in an attempt to improve outcomes. This process, the authors write, is most often left to clinical judgement and is absent from many treatment guidelines.

The authors call for greater attention for deprescribing and the need for RCTs specifically designed to tease out the benefits of the practice.

“At present, deprescribing receives insufficient attention, and there is a great need for the deprescription process to be based on objective evidence rather than solely on subjective clinical judgment,” the authors write.

Problem of Polypharmacy

The authors devote a section of their review article to polypharmacy, which refers to taking multiple medications at the same time. Among women 65 and older in a U.S. survey the authors cite, 23 percent took at least five medications, and 12 percent took at least 10.

Heart medications specifically, the authors write, represent the most used drug class in polypharmacy cohorts. What’s more, heart medications are the most frequent cause of adverse drug events in older patients.

“Polypharmacy increases healthcare costs and the risks of noncompliance and of adverse drug reactions, which is enhanced by both drug–drug and drug–disease interactions,” the authors write.

The problem seems to lie in the very nature of heart disease treatment calling for multiple prescriptions, the authors write, especially in the elderly. Rather than replacing one medication with another, status quo instead calls for the addition of more drugs to treat coronary heart disease. Furthermore, this status quo for therapy is often used as the backdrop against which new drugs are tested via RCTs, the authors write.

“This process leads to polypharmacy because newly licensed prescription drugs are continually introduced, whereas older drugs are not commonly reassessed, and therefore, stay in use,” the authors write.

Drug-Gene Interactions

One topic missing from the review article was the issue of drug-gene interactions. Two of four heart drug classes the authors mentioned are metabolized by highly genetically variable liver enzymes.

The liver enzyme CYP2D6 handles a number of beta-blockers, such as the high-blood pressure medication metoprolol. About 7 percent of the population creates little to none of this enzyme (poor metabolizers), about 35 percent create half of what is expected (intermediate metabolizers), while 7 percent has a super-fast-acting form (ultra rapid metabolizers). These variations could lead to adverse drug events, or drug ineffectiveness.

The enzyme CYP3A4 processes roughly 50 percent of all medications, including some statins, which are used to lower cholesterol. Approximately 8 percent of the Caucasian population has decreased CYP3A4 activity, which could lead to higher-than-normal drug levels in the blood.

These potential interactions involving genetics further increase the risk of adverse effects and other unintended drug treatment consequences, especially in the elderly. Additionally, the effects of polypharmacy can be compounded by age-related biological differences in how the elderly respond to drugs, further increasing the risk of these unintended consequences.

The authors provide a number of recommendations to improve cardiac patient care, especially in the elderly. These recommendations focus on the need for updated real-world RCTs that scrutinize and tackle the complex issues of long-term follow-up, polypharmacy and deprescribing. Perhaps a greater understanding of drug-gene interactions in the heart disease space should be added to this list.

Check out the full article here, and an opinion piece discussing the findings here.