Polypharmacy: An Obvious Problem in Need of Attention

John Mandrola


September 18, 2015

David Foster Wallace famously urged the Kenyon College class of 2005 to notice the obvious. The late American writer began his "This is Water " speech with a fable in which an elder fish greeted two younger fish by asking: "Morning boys, how is the water?" Moments later, one younger fish asked the other: "What the hell is water?"

It's time for those of us in cardiology to pause and make an effort to notice our water.

Current trends have me concerned. I recently admitted an elderly man with life-changing complications, not from his disease but from his guideline-directed pills. This happens too often.

Our "water" now includes ACE inhibitors, angiotensin-receptor blockers (ARBs), beta-blockers, antiplatelet drugs, aldosterone-blockers, loop diuretics, and maybe anticoagulants. And that's only for heart disease; many patients have other diseases. How does a person eat food while swallowing all these pills?

And look at what is coming: an expensive and more potent BP-lowering heart-failure drug, an add-on rate-slowing drug for heart failure, an even more expensive injectable to treat LDL cholesterol (a mere risk factor), and possibly a polypill. The recent press release without results [1] from the SPRINT investigators suggesting more aggressive treatment of high blood pressure will no doubt lead to even more drug prescriptions.

What is real and obvious to me is that our water may contain too many pills.

I am not alone in thinking this. A paper published last week in the Journal of the American College of Cardiology addressed the problem and sequelae of long-term use of cardiac medications.[2]

This beautiful review, from Drs Xavier Rossello (University College London), Stuart Pocock (London School of Hygiene and Tropical Medicine), and Desmond G Julian (Netherhall Gardens, London) expresses concern with the blind certainty of the status quo.

The authors focus their argument on the use of the big four cardiology drugs—aspirin, beta-blockers, ACE inhibitors, and statins—after STEMI. These are the untouchables, the "baseline" therapy." Nothing speaks to the status quo more than the big four drugs.

Randomized clinical trials (RCTs) established benefits of each of these classes of drugs. Patients with STEMI are rightly started on the medications. The default has been to continue treatment indefinitely. Patients keep living. And the result has been that millions of people now take these drugs for years—sometimes decades—longer than any clinical trial was conducted.

That is the issue: Do these drugs confer benefit indefinitely? Haven't you ever wondered about this patient: an 80-year-old who suffered an MI 10 years ago. He was put on the big four drugs. Year after year he reports in for checkups. He's okay, but each year he looks a little frailer; he's more forgetful; he has a walker now after his knee replacement. When is it time to choose to think about whether the harms of these medications outweigh their benefits?

In fact, harm was the main reason the authors cite for writing this review. Dr Desmond Julian suffered life-threatening bradycardia from beta-blockade, a cough from an ACE inhibitor, and aspirin-induced GI bleeding—he had taken these drugs safely for more than a decade before they caused harm.

Their thesis was that the net benefit of cardiac drugs may not remain over the long term, especially into old age. The authors began with a critical appraisal of the evidence supporting use of these meds over the long term.

Four Big Gaps in Knowledge

The first gap is the short-term duration of clinical trials vs the long-term use of drugs in the real world. Here, the statins are closest to "long term," with many of the RCTs having almost 5-year follow-up. A meta-analysis of 82 RCTs of beta-blockers, however, had a mean follow-up of only 1.4 years. Does the benefit seen over 1 to 4 years extrapolate to a decade or more?

The second gap is the assumption of a stable hazard ratio. Most RCTs enrolled patients soon after MI, a time when risk is high and drugs stand to benefit most. After cardiac healing occurs in the months or years to come, the risk of bad outcomes decreases. Does drug benefit continue?

A third knowledge gap involves history. The RCTs of the big four drugs were done in a different era. Did you know the median publication year of the 82 beta-blocker trials was 1982?

Here it is worth thinking about basic physiology. Why did beta-blockers and ACE inhibitors improve outcomes after MI in the pre-PCI era? My idea: before PCI, patients with MI were not rescued from injury and often succumbed to the complications of acute and chronic LV injury. When in this last time you've seen a patient with an LV rupture or ventricular septal defect? Unloading drugs and sympathetic blockers conferred benefit in that era because they protected patients from LV damage. Does that same benefit occur now when so few MIs are left unreperfused?

The final gap is the issue of extrapolating results of trials done in younger patients to the elderly. This is a key issue for today's doctors, because our population is aging and the benefit/risk ratio of cardiac drugs lessens in older, sicker patients. Drug-drug and drug-disease interactions come into play more often in older patients with declining organ function (think sinus-node disease), impaired drug clearance (think chronic kidney disease), and multiple prescriptions (think NSAID use in cardiac patients with arthritis).

Drug-Approval Challenges

The next section of the paper explored how today's drug-approval process worsens polypharmacy. Most new drugs must be tested as add-ons to "standard of care." Ivabradine (Corlanor, Amgen), for instance, was added on to beta-blockers. The failure of head-to-head comparisons leads to yet another medication added to baseline therapy. If you have discharged a patient with new-onset heart failure, you know what I mean. The authors call on regulators to take a broader vision of whole-patient care.


Many paragraphs were devoted to the new-age problem of polypharmacy. Its root cause, the authors say, is one-disease–one-treatment thinking—which prevails with rare exception in most guideline statements. As patients accumulate diseases, each of these conditions has guideline-directed drug recommendations. The authors cited a shocking study[3] in which nearly a quarter of American women older than 65 take at least five prescription drugs. The polypill may only worsen this problem.


One of my favorite topics in the paper addressed the new action verb—deprescribing. Deprescribing gets to the core of doctoring because it requires seeing a person, not her diseases. The problem now, the authors say, is that deprescribing is guided by clinical judgment rather than evidence. That should change. They call for clinical trials for withdrawal of medications. They even give an example of how such a study could be done.


In the final section, the authors urge all parties to close the circle. Evidence on the long-term benefits of drugs is lacking because drugs are approved on the basis of short-term studies. Industry isn't going to conduct research on how to limit its products' use. But if regulators based approval more on a model of whole-patient long-term care then there would be a stimulus to generate such evidence. And this sort of new thinking won't happen unless professional societies, research communities, and caregivers like you and me call for it.

As David Foster Wallace suggested, letting go of natural defaults requires a conscious effort. I used to think that patients in my ICD clinic live on and on because of the big four heart drugs. When I look critically at the short-term outdated evidence, I can't help but wonder whether they live on despite the medications.

Now more than ever we must notice the water.



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