COMMENTARY

Jun 25, 2021 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

June 25, 2021

Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast.

In This Week’s Podcast

For the week ending June 25, 2021, John Mandrola, MD comments on the following news and features stories.

COVID

COVID cases in the United States remain low. People here in Louisville have almost forgotten about COVID, but I have friends who moonlight in rural areas of Kentucky and they say there are still some COVID hospitalizations in unvaccinated people. I had lunch with an ID colleague this week and he said neither he nor his partner have seen even one inpatient with COVID who was vaccinated. I read that even NYC is doing great with COVID cases. I think it’s a testament to the efficacy of the vaccines.

A slight concern is that I noticed that the European Union and United Kingdom have seen a rise in cases. A colleague in France sent me graphs on hospital and ICU admissions there, and there is no spike. But we should keep an eye on that—especially with the Tour de France starting this weekend.

Vaccine-Related Myocarditis

A group from the Centers for Disease Control and Prevention (CDC) presented data from the vaccine adverse event reporting system to the US Food and Drug Administration (FDA) this week. As I discussed last week, the signal of myocarditis from mRNA vaccines is almost certainly strong enough to make causal claims—mainly because the observed cases are so much greater than the expected.

Not much of this is news. What made news this week was the online debate about the conclusions of the CDC panel, which were strongly in favor of giving the vaccine to adolescents and young adults, even if they had had myocarditis or pericarditis before the first shot. CDC director Rochelle Walensky Tweeted:

If we vaccinate 1 million 12-17 year-olds, we could see 30-40 MILD cases of myocarditis. In this same 1 million, through vaccination we AVOID: 8,000 cases of COVID-19, 200 hospitalizations, 50 ICU stays & 1 death. The benefits far outweigh the risks.

There is so much to disagree with here:

  • First, while I agree that myocarditis severity comes on a spectrum, I read the myocarditis reports. Many of these were hardly mild. There were big troponin levels and ICU admissions. And these are in healthy kids; this is a preventive therapy of a very low-risk disease (for kids). Calling myocarditis mild reminds me of the saying about minor surgery. Minor surgery is surgery done on someone else. Similarly, mild myocarditis only occurs in other folks’ kids.

  • Second, citing COVID numbers like that assumes that rates of hospitalization and illness with COVID will be the same as it was in 2020. COVID morbidity and mortality going forward seems highly uncertain.

  • Third, people don’t calculate risk like this. If they did, we wouldn’t have problems with low anticoagulation (AC) uptake in patients with atrial fibrillation (AF). People feel risk. Some fear the AC as much as the stroke, despite the data.

So, a lot of rational people will look at the risk of their kid getting seriously ill from the vaccine and want to take their chances with the virus. Other parents will feel more risk from the virus. That is how medical decisions should be made: with judgement and risk-harm balances and considerations of special circumstances. I strongly believe that at this point (emphasis on now, with only early safety data in kids) this ought to be up to the parents and patients to decide.

To be clear. I absolutely 100% love the vaccine for older adults and those with risk factors from COVID, or for those who simply want the protection. But for young people, we have time to wait for more data, consider different regimens of vaccination, have shared decisions. Time will help sort out different regimens in kids, lower doses, one shot, delaying shots after recent COVID infection, etc. It boggles my mind that schools and colleges would be allowed to mandate a vaccine that could cause a serious heart condition—in the current climate of so little COVID-19. The good news is that the US Food and Drug Administration (FDA) is finalizing language on a warning statement for healthcare providers, vaccine recipients, and parents or caregivers of teens.

Lipid Guidelines

The headline says: Clinicians Slow to Implement Lipid-Lowering Guidelines. This from a JAMA-Cardiology paper that used the GOULD registry for its study. GOULD stands for Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management and it is a multicenter registry of patients with documented vascular disease. We are looking at secondary prevention.

The study included about 5000 patients. To get into the registry, you had to be in one of three groups: on a PCSK9 inhibitor drug, have an LDL cholesterol (LDL-C) level greater than 100 mg/dL, or have an LDL between 70 and 99 mg/dL. The mean age of these patients was about 67 years. They were mostly white with a body mass index of about 30. Recall that the most recent guidelines recommend intensifying therapy if the LDL is above 70 mg/dL. Intensifying therapy could mean more statins, more potent statins, adding ezetimibe or a PCSK9 inhibitor.

The authors, led by Chris Cannon, from Brigham and Women’s Hospital in Boston, reported quite low levels of intensification of therapy.

  • The topline result was that at 2 years, only 17.1% of these patients with established heart disease had intensification of lipid-lowering therapy;.

  • Two-thirds of the patients remained at an LDL-C of more than 70 mg/dL;

  • Teaching hospitals seemed to do slightly better;

  • Lipid protocols helped increase the amount of lipid intensification;

  • Cardiologists were more likely to intensify compared with internists.

The first thing to say is that this is a nice use of registries. Remember the saying: Science tells us what we can do; trials tell us what we should do; and registries tell us what we are doing. I love that the authors made no causal conclusions.

Second, I always get slightly un-nerved when reading comments like this: "This is yet another disappointing reminder of how we are failing our patients”

This was a quote from Dr. Ann Marie Navar from Duke. I have a ton of respect Dr. Navar and her work, but this comment bothers me, and here is why: Intensification of therapy is a preference-sensitive decision. Everyone agrees that taking more of a pill, taking another pill, or an injection in the case of PCSK9 inhibitors, is a decision to be discussed with a patient.

I find it problematic to promote shared decisions and then recoil that too few patients are taking a therapy. (This happens often with AC: guidelines give shared decision making a Class 1 recommendation, then they say AC is underused.) It’s the same with lipid-lowering therapy.

While I agree that a higher-intensity statin, or ezetimibe, or pCSK9 inhibitors do indeed reduce the risk of future cardiac events. It is also true that from an individual patient’s view, in absolute terms, the risk reduction is small.

  • In the IMPROVE-IT trial, ezetimibe/simvastatin reduced the major adverse cardiac event (MACE) endpoint by 2%. But the control arm was simvastatin, and there were no differences in death, or cardiovascular (CV) death. And these patients were post-acute coronary syndrome (ACS), a clearly higher risk group.

  • The differences were also small in the PCSK9 inhibitor trials: in the ODYSSEY outcome trial, with alirocumab, the absolute difference for a MACE outcome was only 1.6%, and again, no significant differences were noted in death or CV death. Again, these were patients who were post ACS.

  • Recall also the point my friend Dr. Luis Corriera often makes: these absolute risk reductions are average and probabilistic. As a patient, you have no idea whether or not you will get any benefit from the extra therapy.

Older patients (here in their late 60s) with documented vascular disease often have other medical problems. Many of these patients have issues with co-morbid conditions and pill burden. Intensifying medical therapy may be no big deal for some, but for others, it’s another pill and more costs.

Here I think about what Mayo Clinic cardiologists Victor Montori teaches, which is minimally disruptive care. You have to prioritize. Effort and cost spent on another lipid drug risks distracting effort from some other problem. Some of these other problems may be more important to the patient than a preventive pill that has no effect on how they feel.

Finally, I am totally for doing everything we can to reduce adverse outcomes, but I think we should be at least a little skeptical about studies that document that real world care is harder than care in the confines of a trial. Trials are a long way from real world practice.

Financial Toxicity of Heart Disease Therapeutics

A paper from Houston Methodist DeBakey Heart and Vascular Center reports that financial toxicity—things like trouble paying bills, delaying care due to costs, nonadherence to meds—is greater in patients with heart disease than those with cancer. That result surprised me. While it is very common—almost daily—for me to hear from patients about costs, I would have guessed that cancer care was worse.

The authors used a National Health Survey of adults who self-identified as having atherosclerotic cardiovascular disease (ASCVD). The survey included 140,000 patients and the paper considered about 6000 patients who had ASCVD, 6,887 who had cancer, and about 1000 who had both. In general, financial toxicity was about 25% more common in those with ASCVD.

The paper has plenty of limitations; it’s specifics aren’t as important as the message: It may seem nutty to my international listeners who hail from countries with a national healthcare system, but here in the United States, financial toxicity is a huge problem and it’s getting worse. It is not just the very poor who are affected, it’s the working poor.

Consider a private contractor who depends on his work; he barely makes enough to cover a catastrophic health plan with high deductibles. He has an MI and a stent. Boom—the hospital stay covers his huge deductible; but now he has to pay for his meds. I don’t care what his LDL is on 80 mg of atorvastatin. There is no way he is paying for PCSK9 inhibitor. Then, what if he develops AF from the stress? Now we want him to take apixaban. Boom, another $400 every month.

I am not a policy wonk nor a public health doc. I am merely a clinician trying to use the best therapies possible. But increasingly, it is simply impossible for people to afford care. I am not optimistic that Americans will ever see the wisdom of a Canadian or UK system. Why? Because Americans are not used to people saying no, we can’t afford to pay for this or that dubious therapy.

Statins in the Elderly

Regular listeners of this podcast know that I am a fan of deprescribing to reduce pill burden. Older patients who are nearing end of life should eat food not pills.

Italian authors from the Lombardy region have published an observational study that finds that discontinuing statins in older patients was associated with an increased risk of hospital admissions for heart failure, any CV outcome, or death. The lead author Frederico Rea said this in a news article on theheart.og | Medscape Cardiology: Statins are "lifesaving" drugs, and "according to the findings of our study, the discontinuation of this therapy has significant effects. Note the causal language: “the discontinuation... has significant effects.” I will tell you what they did, and what they found, and then why this is bullocks.

The data came from utilization databases in Lombardy. They used diagnostic and therapy codes. First, they identified patients receiving polypharmacy (four drugs), about 29,000 patients; mean age 76 years. Then they compared the outcomes among those who stopped the statin vs those who did not. 23,000 patients maintained the drug, 5800 patients stopped it.

Of course, patients who did and did not stop statins differed in characteristics, so the authors did a propensity matching, where they tried to balance stoppers and nonstoppers on the bases of characteristics that you can put in a database—characteristics such as cancer, brain disease, kidney disease etc. They even used a co-morbidity score to try to balance the groups. Note that this was not a randomization, a doctor or patient or both decided to discontinue the statin.

The main finding was that patients who stopped the statin had a higher rate of heart failure (HF) admissions, any CV outcome, and death.

My observations:

  • This is a problematic paper. To be fair, the authors recognize the main problem--confounding—in the limitations. What I mean by confounding is that patients who decided (for whatever reason) to stop their statin likely differed from those who did not stop the statin. And those differences are the likely causes of worse outcomes.

  • Authors of observational studies use statistical models and try to propensity-match to simulate the balancing of groups that randomization usually accomplishes, but statistical tools can only use data that is on a spreadsheet. We all know that many important patient characteristics do not show up on spreadsheets.

This is likely in this case. For instance, the strongest effect of statin discontinuation was an increase in HF admissions; but statins should have no effect on fluid overload syndromes. In fact, the GISSI HF and CORONA RCTs of statin use in patients with HF showed no benefit of the drugs.

Why would the biggest effect be for HF admissions? Because stoppers were sicker than nonstoppers, and that is why they had worse CV outcomes and death.

My feelings about statins have evolved over the past decade:

  • I now believe the ample RCT evidence with these drugs clearly show that the drugs reduce CV outcomes over the long run by about 25%. In absolute terms it is a small probabilistic decrease. If that is important to patients, fine. They can take them.

  • I also strongly believe that as multimorbidity increases, there are multiple other competing causes of poor outcomes, and the net benefit in overall health of preventing only one type of bad outcome is less.

I often tell people in their eighth and ninth decades that the point of preventive meds was that taking them in their 50s and 60s helps them live to old age. Now, in old age, the drugs may be more burden than help. One of the dumbest things in all of Medicine is when I see a cachectic dying patient with any disease still taking the statin. We should always be looking to deprescribe wisely, and this study does nothing to change that.

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