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Top 10 Cardiology Stories of 2018

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1. The Apple Watch Experiment

“It had to start somewhere,” said Gopi Dandamudi, MD, from CHI-Franciscan Health Pacific Northwest. On the basis of two unpublished studies, the US Food and Drug Administration (FDA) cleared Apple to enter the healthcare space. The release of the ECG app for the Apple Watch begins a grand experiment in screening for disease.

Perhaps the most remarkable part of this experiment is not its size but its leadership. Patients, not doctors, are in charge. Is this the beginning of what Medscape’s editor-in-chief, Eric Topol, called The Creative Destruction of Medicine?[1]

I love Apple products, but I am pessimistic about the ECG app. While brilliant advances have made this a great time to be sick, it’s a bad time for people without disease to interact with healthcare. I predict that the mixture of fear, fee-for-service models, overburdened clinicians, and a poor understanding of the normal variations of the heart rhythm will lead to a tsunami of iatrogenic harm in the short run.[2]

2. Treating Hypertension in the Community

Speaking of healthcare led by nonphysicians, here is the conclusion of the late Ron Victor’s cluster randomized trial  of blood pressure reduction: “Among black male barbershop patrons with uncontrolled hypertension, health promotion by barbers resulted in larger blood-pressure reduction when coupled with medication management in barbershops by specialty-trained pharmacists.”[3]

This conclusion understates the effect size. The mean systolic blood pressure fell by a massive 27.0 mm Hg (to 125.8 mm Hg) in the intervention group and by 9.3 mm Hg (to 145.4 mm Hg) in the control group; the mean reduction was 21.6 mm Hg greater with the intervention (95% confidence interval, 14.7 to 28.4 mm Hg;  P < .001).

Results of the FAITH trial, another cluster-randomized trial—of black churches—confirmed the efficacy of a community-centered approach to health.[4] In FAITH, motivational interviewing plus lifestyle interventions by lay health advisors resulted in significant blood pressure reductions compared with usual health education at 6 months.

For me, the worst aspect of US healthcare is the injustice. While overtreatment proliferates in wealthy enclaves, underserved populations, such as black men in urban areas, suffer needless morbidity from something as easily treated as high blood pressure. The genius of the barbershop approach is that it shows the feasibility of new models of care. Ron Victor and Anthony Reid leave a great legacy; we need to continue this work.

3. Aspirin Flops for Primary Prevention

This year, three large randomized controlled trials (RCTs) comparing aspirin at 100 mg to placebo for the prevention of cardiac events in people without heart disease told a clear story.

The 7-year ASCEND trial enrolled more than 15,000 patients with diabetes and found that aspirin reduced cardiac events by 1.1% but increased major bleeding by 0.9%.[5] The 5-year ARRIVE trial  enrolled more than 12,500 patients with moderate cardiac risk and observed no significant difference in cardiac events but a twofold greater risk for gastrointestinal bleeding in the aspirin arm.[6] In the more than 19,000 elderly people followed for nearly 5 years in the ASPREE trial,   aspirin did not prolong disability-free survival and was associated with a higher rate of bleeding and a statistically significant 1.5% higher rate of death.[7,8,9]

This medical reversal teaches two lessons. One is simple: Don’t use aspirin in patients without heart disease. The more important lesson pertains to the importance of contemporary clinical trials. The combination of better baseline therapies (statins) plus the secular decline in cardiac event rates makes it much harder for any therapy to show benefits. When applying evidence at the bedside, favor newer trials.

4. MitraClip Uncertainty

Two trials published this year reported utterly divergent results for percutaneous repair of secondary mitral regurgitation (MR) with the MitraClip device. The 12-month-long MITRA-FR trial  showed no difference in a composite primary outcome of death or heart failure hospitalization.[10] The 24-month-long COAPT trial  showed a massive absolute risk reduction of 32% for the primary endpoint of heart failure hospitalization and an absolute reduction in death (secondary endpoint) of 17%.[11]

Proponents of MitraClip explain these differences with four arguments: Medical management in COAPT was more aggressive, which meant it enrolled truly refractory patients; COAPT enrolled patients with more severe MR and less dilated ventricles, which means their left ventricle had not yet passed the point of no return; procedural complications were lower in COAPT (8.5% vs 14.6% in MITRA-FR); and the operators were more effective in reducing MR, as seen in the number of patients with residual MR of 3 or greater (5% vs 17%).

I am not convinced patients in these two trials were that different. A comparison of baseline characteristics suggests that the average patient was similar; grading of MR and left ventricle dimensions are hardly an exact science, and the 1-year death rates of the control groups of both trials are close: 22.4% in MITRA-FR and 23.2% in COAPT. I see equipoise.

The truth about cardiac devices is that once they are approved and reimbursed, optimistic cardiologists will use them. Look at Watchman uptake despite dubious data. Being wrong about MitraClip could be a massive blunder. Before expanding the indications for this device, FDA regulators should wait for two more pieces of data: 2-year results of MITRA-FR and the results of RESHAPE-HF, the third RCT of MitraClip in patients with secondary MR.

5. Stop and Think About Methods Uncertainty

Many variables affect the results of a study. The research question posed, inclusion/exclusion criteria, comparator, and endpoints are obvious factors. I had always thought the analysis of the data was rote and that one set of data led to one result. I was wrong.

Brian Nosek, PhD, and his team at the University of Virginia have shown that choices made in the way a set of data is analyzed can lead to substantial variation in effect sizes.[12]

In the “Many Analysts, One Data Set” paper they recruited 29 teams of experienced researchers to analyze one large data set in an effort to answer one simple question: Are soccer referees more likely to give red cards for foul play to dark-skin–toned players? They found that each team made a unique choice in how they would analyze the data, and, crucially, these decisions led to statistically positive results two thirds of the time and negative results the rest of the time.

Given the coming revolution in “big data” and the fact that most medical science turns on frequentist techniques (eg, the P value), this previously under-recognized variance has great importance for clinicians.

Perhaps we are on the cusp of change in data analysis. In April, John Ioannidis, MD, DSc, from Stanford University, wrote in support of lowering the P value cutoff for significance in medical studies from .05 to .005.[13] He called this a temporary fix until more durable solutions to data analysis are adopted.

The next time you see a small effect size, a P value close to .05, or a change in a trial’s endpoints, go back and revisit Nosek and colleagues’ paper and their discussion.

6. The Ischemia Trial, Faith Healing, and Subtraction Anxiety

The debate earlier this year over changing endpoints of the still-ongoing ISCHEMIA trial gifted cardiology a trove of lessons. The ISCHEMIA trial will compare the initial strategy of percutaneous coronary intervention (PCI) plus medical therapy vs medical therapy alone in patients with stable coronary artery disease. The original trial plan boasted a true test of efficacy by measuring two hard endpoints: cardiovascular death and myocardial infarction (MI).

The design and size (more than 5000 patients) of ISCHEMIA make it the final test of PCI in patients with stable coronary disease. The key feature of this trial addresses persisting criticism of COURAGE:[14] namely, all patients had to have documented moderate (or greater) ischemia on stress testing.

In January, as the trial was nearly done recruiting, ISCHEMIA researchers amended the primary endpoint to a five-component composite of cardiovascular death, nonfatal MI, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure. They explained  that this change was described in the original protocol, done at the direction of an independent data committee and necessary to prevent underpowered results from low event rates.[15]

This news stimulated one of the most clinically relevant editorials I have ever read. In “Faith Healing and Subtraction Anxiety,”[16] Christopher Rajkumar, MBBS, and colleagues at the Imperial College London explain how human belief systems affect decision-making. And why these beliefs make it vital to have bias-proof endpoints in unblinded trials.

Using the example of two studies on fractional flow reserve,[17,18] the editorialists explained that the simple act of telling patients that their physiology test indicated no artery obstruction dramatically improved symptoms. In the DEFER trial, for instance, the number of patients reporting chest pain was reduced from 88% to 54% after patients heard their lesion was not obstructive. Take-home: Our beliefs (faith) can help people feel better.

Subtraction anxiety exerts the opposite effect. When doctors believe that PCI “fixes” people, there is anxiety over not having it. Rajkumar and colleagues point to the positive FAME-2 trial, in which the composite endpoint was driven not by MI or death but by higher rates of revascularization in the medical (or stent-subtracted) arm. Take-home: Our beliefs can trump evidence and can impair our ability to conduct unbiased trials.

7. Fish Oil Finally Wins

Until Deepak Bhatt, MD, from Harvard University presented the stunningly positive REDUCE-IT trial,[19] nearly 80 studies of fish oil supplementation had failed to show any benefit.[20]

But In REDUCE-IT, a high dose (4 g daily) of purified eicosapentaenoic acid used in patients with high triglyceride levels reduced a composite of major cardiac events by almost 5% in absolute terms. All components of the composite endpoint were significantly reduced. Also remarkable was that these patients were receiving statin therapy and had median low-density lipoprotein cholesterol levels of 74 to 76 mg/dL.

Three factors caused skepticism over REDUCE-IT: One was its outlier nature; another was the unknown mechanism of benefit; and the third was concerns about potential harm from the mineral oil placebo, which was associated with significantly higher levels of non-high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and apolipoprotein B.

My take is that the (purified) brand and dose of fish oil plus the selection of patients with high triglycerides were enough to explain the results. During an interview,  Professor Jane Armitage from Oxford thought that REDUCE-IT would apply to about 30% of patients with high triglyceride levels. She reminded me of something doctors often forget: The best way to reduce one’s triglyceride levels is with diet and exercise. Prescription-strength fish oil will likely be expensive. We will see how this influences uptake.

8. Turn Down the Oxygen

When patients are sick and struggling to get enough nutrients to their organs, I have always cranked up the oxygen. This seemed like a no-brainer; hypoxemia is bad.

Researchers from McMaster University proved me wrong. In their meta-analysis and systematic review of 25 RCTs, which included more than 16,000 patients with sepsis, critical illness, stroke, trauma, MI, or emergency surgery, a liberal oxygen strategy was associated with an increase in mortality compared with conservative use.[21]  Low heterogeneity of the included RCTs and a meta-regression showing that trials using higher doses of oxygen had higher mortality rates bolstered confidence in the results.

Two messages: Whether the mechanism of harm from too much oxygen is due to free radicals, inflammation, or perhaps delayed recognition of deteriorating patients does not matter. What matters is that higher doses of oxygen cause harm and we should change our practice. This stunning reversal also confirms the value of using evidence in the care of patients. It reminds us of the wisdom of the late physicist Richard Feynman:  “The first principle is that you must not fool yourself, and you are the easiest person to fool.”

9. The Good News About the PREDIMED Retraction

In the grand scheme of heart health, the food we eat todos los dias has greater importance than any drug or device. Nutrition evidence, however, is plagued by weak science. In the mass of confounded observational studies, the RCT called PREDIMED[22] stood out as good nutrition science.

In 2013, PREDIMED authors reported that eating a Mediterranean diet supplemented with nuts or olive oil vs a regular Spanish diet led to a 30% lower rate of cardiovascular events. PREDIMED’s more than 2100 citations confirmed its influence.

When the New England Journal of Medicine  (NEJM) retracted and republished a revised PREDIMED study[23] this year because of irregularities of randomization, discovered by the British anesthesiologist John Carlisle, it was easy to be cynical.[24]  But I agree with outgoing NEJM editor-in-chief, Jeff Drazen, MD, who wrote that their “[PREDIMED] review did not alter any conclusions and should raise public trust in science, not erode it.”

Here’s why: John Carlisle’s work on analyzing baseline characteristics  to assess for adequate randomization taught researchers and journal editors an important lesson. Also, the PREDIMED authors handling of the issues was exemplary; they investigated the problem, wrote clearly about it, and did vigorous statistical analysis to account for the irregular randomization.  While the new analysis may weaken our confidence in the benefits of a Mediterranean diet, this story advances confidence in science.

10. AF Ablation Questions Remain

In 2018, two large RCTs addressed hard outcomes after atrial fibrillation (AF) ablation. You would think this much evidence would have provided clarity about a common procedure. I don’t think so.

The CASTLE-AF trial assigned about 360 patients with heart failure and AF to ablation or medical therapy.[25]  Ablation was associated with a 38% relative reduction in the primary outcome of death from any cause or hospitalization for worsening heart failure. This translated to a 16% reduction in absolute terms, with a number needed to treat of 6. Ablation lowered the overall death rate by 47% (13.4% vs 25%).

While this looks impressive, reasons for caution include that the trial was terminated before it reached its prespecified targets, the number of patients lost to follow-up was large, and the primary analysis was based on a handful of events. External validity of CASTLE-AF is also limited. Enrolled patients were 64 years old on average, were mostly male, and had a median left ventricular ejection fraction of 32%. For every patient like this, I see 20 who are older, sicker, and too frail for an invasive procedure.

Douglas Packer, MD, from the Mayo Clinic presented results of the CABANA Trial of AF ablation vs medical therapy in May, but the paper is not yet published. In this RCT of 2200 patients with symptomatic AF and at least one risk factor, the 14% lower rate of the composite endpoint of death, stroke, bleeding, or cardiac arrest in the ablation arm did not meet statistical significance.

The debate on CABANA turns on the analysis by treatment received, which markedly favored ablation. Because many patients in the medical arm crossed over to ablation, the question is how to square the nonsignificant intention-to-treat findings with the super-positive as-treated analysis.

Conclusion

I had oodles of fun this year. I’ve always loved being a doctor, but reading, writing, and thinking about medical science has made it even more gratifying. I feel blessed to work with the team of professionals here at theheart.org

Source:Medscape Cardiology.

 

Lp(a) Levels May Modulate CV Benefits of Evolocumab: FOURIER

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Patients treated with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen) may experience a greater reduction in cardiovascular events if they have higher baseline levels of lipoprotein(a) [Lp(a)], US investigators have shown.

The results are from a preplanned analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, published in March 2017 in the New England Journal of Medicine.

As reported by theheart.org | Medscape Cardiology at that time, main FOURIER results showed that evolocumab was associated with a 15% reduced risk for a composite of myocardial infarction (MI), stroke, cardiovascular disease (CVD), coronary revascularization, and unstable angina hospitalization at 22 months compared with placebo (P < .001).

Moreover, treatment was associated with a 20% reduction in a composite of CVD, MI, and stroke vs placebo (P < .001), which occurred in tandem with large reductions in low-density lipoprotein (LDL) cholesterol levels.

The current analysis, presented here at the European Atherosclerosis Society (EAS) 2018 meeting, shows evolocumab also achieves significant reductions in Lp(a) levels of more than 25%.

The researchers found that the greatest effect of the drug compared with placebo on the risk for cardiovascular death, MI, and stroke was in patients with higher baseline Lp(a) levels, at 24% vs 15% in those with lower levels, at a twofold increase in the absolute risk reduction.

Study presenter Michelle L. O’Donoghue, MD, Brigham and Women’s Hospital, Boston, Massachusetts, told theheart.org | Medscape Cardiology that whether or not the benefits offered by Lp(a) reduction are “above and beyond” the LDL reduction is an area of ongoing study.

“But I think it’s worthwhile that we were able to see that baseline Lp(a) concentration appears to help identify individuals who derive greater benefit from treatment with evolocumab,” she added.

“So if those individuals have a larger magnitude of benefit and a smaller number needed to treat, then that’s perfect, as we’re trying to think about different high-risk features that might help to identify individuals who get the greatest benefit from the drug in a cost-effective manner.”

For O’Donoghue, one of the key aspects of their results is that they suggest that evolocumab affects both Lp(a) and LDL separately to lower the risk for cardiovascular outcomes. This was underlined by data showing that the greatest benefit was seen in individuals who achieved both their Lp(a) and LDL cholesterol target.

“With a drug like evolocumab, you’ve got multiple effects, and it becomes almost like a pleiotropic effect, because you’ve got LDL lowering, which is obviously very compelling, in addition to the effects on Lp(a),” she said.

“I think there’s a lot of work to be done to figure out whether or not the Lp(a) reduction on its own offers as much, or greater, or less benefit than LDL reduction on its own,” she added. “It’s interesting to see, though, that those who achieved the dual targets of lower levels of both are those who do best.”

Evolocumab and Lp(a)

The FOURIER trial involved 27,564 patients with stable atherosclerotic CVD and LDL cholesterol levels of 1.8 mmol/L (70 mg/dL) or higher who were receiving statin therapy and were randomly assigned to evolocumab, 140-mg injections every other week or 420-mg injections monthly, or to placebo.

After a mean follow-up of 2.2 years, evolocumab treatment was associated with a 59% relative reduction (P < .00001), or a 56-mg/dL absolute reduction, in LDL levels down to a median of 30 mg/dL, alongside the observed clinical benefits.

Previous Mendelian randomization data suggested that Lp(a) plays a causal role in the risk for coronary heart disease (CHD), and PCSK9 inhibitors have been shown to significantly reduce Lp(a) levels, so the team examined the impact of evolocumab on Lp(a) in FOURIER.

As part of the trial, Lp(a) levels were measured at baseline and weeks 12 and 58, with results available for 25,096 participants. The median Lp(a) level was 37 nmol/L (interquartile range [IQR], 13 – 165 nmol/L).

Individuals in the highest quartile of Lp(a) levels were, compared with those in the lower quartiles, significantly less likely to be male, to have ischemic stroke and diabetes mellitus, and to currently use tobacco (P < .001 for trend).

In contrast, individuals in the highest quartile were significantly more likely to have had a MI, to have peripheral artery disease, and to have higher baseline LDL cholesterol levels than those in the lower quartiles (P < .001 for trend).

As expected, higher baseline Lp(a) levels were associated in the placebo group with a significantly higher risk for CHD death or MI, cardiovascular death, MI or stroke, and MI and coronary death individually on multivariate analyses taking into account a range of potential confounding factors.

For example, the adjusted hazard ratio of CHD death or MI in participants with an Lp(a) in quartile 4 vs those in quartile 1 was 1.26 (95% CI, 1.02 – 1.56).

Among 11,864 participants given evolocumab, treatment was associated with a mean absolute change in Lp(a) levels at week 48 of –11 nmol/L (IQR, –31 nmol/L to –1 nmol/L), or a median percentage change of –26.9% (IQR, –46.7% to –6.2%).

The correlation between percentage change in Lp(a) and change in LDL cholesterol at 48 weeks in treated patients was r = 0.37 (P < .001), while that for absolute change was r = 0.21.

When the team divided the patients into those whose baseline Lp(a) level was above the median and those whose level was at or below the median, they found a difference in the impact of evolocumab on cardiovascular outcomes vs placebo.

Specifically, patients with a baseline Lp(a) level above the median had a hazard ratio of cardiovascular death, MI, or stroke with evolocumab vs placebo of 0.76 (95% CI, 0.66 – 0.86), or an absolute risk reduction of 2.8% and a number needed to treat of 36.

This compares with a hazard ratio for evolocumab vs placebo among patients with a baseline Lp(a) level at or below the median of 0.85 (95% CI, 0.73 – 0.97), or an absolute risk reduction of 1.28% and a number needed to treat of 79.

Next, the team looked at Lp(a) and LDL cholesterol together in terms of the impact of evolocumab treatment on the risk for combined cardiovascular events after week 12.

The risk was lower in patients who achieved a reduction of Lp(a) and LDL cholesterol to at or below the median at baseline (6.57%) than in those who achieved that milestone only with Lp(a) (7.88%), those who got there only with LDL cholesterol (8.45%), and those who achieved that for neither measure (9.43%) (P < .001 overall).

Concluding her presentation, O’Donoghue said their findings show that evolocumab significantly reduces Lp(a) levels and that “patients starting with higher Lp(a) levels appear to derive greater absolute benefit.”

Moreover, individuals “who achieve lower levels of both LDL cholesterol and Lp(a) have the lowest subsequent risk of CV events.”

Speaking after the session in an interview, she said that this latter finding is particularly interesting when one thinks of the individuals who have a reduction in Lp(a) levels “but a rise in LDL cholesterol levels at the same time.”

“What are those genetic predictors that help to identify those individuals? It’s not completely clear,” she said.

Completely Different Story

Commenting on the findings, Alberico L. Catapano, MD, PhD, professor of pharmacology at the University of Milan, Italy, and past president of the EAS, told theheart.org | Medscape Cardiology that “it’s a completely different story” between Lp(a) and LDL cholesterol.

He explained that with LDL cholesterol, the greater the reduction in plasma levels, the greater the benefit, while with Lp(a), “there’s always been a struggle” to demonstrate a similar relationship.

“Lp(a) is related to cardiovascular disease, but the strongest relationship is with calcification of the aortic wall, or aortic stenosis,” he said.

However, Catapano noted that the “exact mechanism is still not completely clear,” unlike the situation with LDL.

“Of course, we’ll never know everything for sure but we have robust evidence with LDL,” he said. “With Lp(a), it’s not clear whether it’s coagulation, whether it’s atherosclerosis and the buildup of cholesterol, or both together.”

“Having said that,” he added, “there is clearly a relationship that is not linear but sort-of hyperbolic, so that above a certain level, the correlation gets stronger and the risk becomes higher.”

Catapano pointed out, however, that the median Lp(a) levels seen in the FOURIER trial were lower than those seen in the general population and lower than the 50 mg/dL that has been linked to a substantially increased cardiovascular risk, “so you would not expect a huge benefit” with Lp(a) reduction in this population.

“The second point is they saw a benefit that was larger in absolute terms according to the levels of Lp(a), [which] is entirely in line with what we know,” he said. “We know that Lp(a) contributes to the risk and we know that we have a higher risk if we have higher Lp(a), and that reducing LDL cholesterol for sure reduces the risk.”

“Whether the contribution of Lp(a) to that reduction of risk is important, we do not know; it would be almost impossible to disentangle from the data,” he said. “That’s my personal view.”

However, Catapano believes, these answers may be provided  with the results of ongoing studies into antisense nucleotides, which target Lp(a) specifically.

FOURIER was funded by Amgen. O’ Donoghue reports receiving research grant support from GlaxoSmithKline, Eisai, Merck & Co, Janssen, Amgen, The Medicines Company, and AstraZeneca. Catapano reports being a consultant for and receiving honoraria from Pfizer, Sanofi, Genzyme, Merck, Akcea, and Amgen; receiving honoraria from Kowa, Mediolanum, Farmaceuti, Menarini, Bayer, Eli Lilly, Recordati, and Genzyme; and receiving research grants from Pfizer, Merck, Sanofi, Menarini, Regeneron, Mediolanum, and Farmaceutici.

 

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Lab-Confirmed Flu Virus Linked to Imminent Risk for Acute MI

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Patients with laboratory-confirmed influenza were about six times as likely to be admitted for acute MI in the following 7 days compared with the period comprising the prior and subsequent years, results of a cohort study show.[1]

The risk was especially pronounced in older patients and was independent of flu vaccination status or history of MI hospitalization. There was also a signal that other forms of respiratory infection can similarly raise the risk for MI admission.

The findings are consistent with a lot of prior research, acknowledged Dr Jeffrey C Kwong (University of Toronto, ON), but much of it associated MI with acute respiratory infections by undetermined pathogens, or with other indirect indicators of flu.

“This is the first one where we used lab-confirmed influenza as the exposure, and we found this association that was quite strong between influenza and MI,” he told theheart.org | Medscape Cardiology.

Kwong is lead author on the study, which was based on Ontario health insurance records of people tested for respiratory viruses from May 2009 to May 2014 and was published January 24 in the New England Journal of Medicine.

The results are “no surprise,” agreed Dr Scott David Solomon (Brigham and Women’s Hospital, Boston, MA), who wasn’t involved in the study. But, he added, “What’s novel here, and improves on prior knowledge, is that it goes down to the individual-patient level, and says that when somebody actually has confirmed influenza, that they are more likely to have an MI.”

Kwong and his colleagues state that the increased MI risk regardless of vaccination status should not be seen as evidence that influenza vaccinations are ineffective; the study wasn’t designed to explore that issue. It does suggest, however, “that if vaccinated patients have influenza of sufficient severity to warrant testing, their risk of acute myocardial infarction is increased to a level that is similar to that among unvaccinated patients.”

The study seems to strengthen familiar public health messages about getting flu vaccinations and taking measures to prevent the spread of respiratory viruses, especially for patients with cardiovascular risk factors. Despite such messages, vaccination rates may be low even in such high-risk groups.

Solomon pointed to a recent analysis based on patients with heart failure in the PARADIGM-HF trial that saw only about a 53% rate of vaccination for influenza in North America.[2]

“And that was surprising because these were people who are clearly at risk, and would clearly benefit from vaccination,” he said.

Even when the effectiveness of the season’s flu vaccination has been questioned, such as the current flu season, “getting some protection is better than getting no protection,” Kwong said.

Secondary prevention patients with heart disease “don’t question taking aspirin, they don’t question taking β-blockers, they don’t question taking blood pressure medications or statins. But a lot of patients question the value of getting a flu shot,” he said.

“If you compare the effectiveness of influenza vaccination in preventing infection to statins in preventing MI, they shouldn’t be having second thoughts about getting a flu shot.”

Seven-Day Risk Interval

The analysis looked at 364 hospitalizations for acute MI in 332 patients that occurred within 1 year before and 1 year after laboratory confirmation of influenza; 48% in were women and 24% of the patients had been previously hospitalized for MI.

Of the 364 hospitalizations, 20 occurred during the first 7 days after the collection of a positive respiratory specimen, termed the “risk interval.” The remaining 344 hospitalizations occurred during the 2-year period made up of the year before and the year after the risk interval, termed the “control interval.”

The risk for MI hospitalization was increased sixfold during the risk interval compared with the control interval. Kwong said the group had expected the risk to fall off gradually, “but we actually saw that it just dropped down to nothing right after the first week. It’s really that first week where the risk is concentrated.”

Table 1. Incidence Ratios for Acute MI Hospitalization by Time After Laboratory Confirmation of Influenza

Interval Incidence Ratio (95% CI)
Days 1–7 6.05 (3.86–9.50)
Days 1–3 6.30 (3.25–12.22)
Days 4–7 5.78 (3.17–10.53)
Days 8–14 0.60 (0.15–2.41)
Days 15–28 0.75 (0.31–1.81)

 

The group also observed increased MI hospitalization risk associated with respiratory samples positive for viruses other than influenza. The implication may be that respiratory infections per se, not simply influenza, are associated with acute MI, according to Kwong.

“I think we just found that influenza risk seemed to be higher than that of the other respiratory viruses.”

Risk associated with influenza B was higher than with influenza A; Kwong said his group doesn’t have an explanation for the difference.

Table 2. Incidence Ratios for Acute MI Hospitalization by Specific Infections

Infection Incidence Ratio (95% CI)
Influenza A 5.17 (3.02–8.84)
Influenza B 10.11 (4.37–23.38)
RSV 3.51 (1.11–11.12)
Noninfluenza virus, non-RSV 2.77 (1.23–6.24)
Illness, no respiratory virus identifieda 3.30 (1.90–5.73)
RSV = respiratory syncytial virus. aFrom among influenza A, influenza B, RSV, parainfluenza virus, adenovirus, human metapneumovirus, coronavirus, or enterovirus.

 

Respiratory infections could trigger MI by any of several possible mechanisms, Kwong and Solomon observed.

Influenza elevates an array of proinflammatory cytokines that can lead to endothelial dysfunction, and possibly plaque rupture, but whether that’s the primary mechanism “is really just a postulate. We don’t know for sure that’s what is contributing,” Solomon said.

People with the flu also have increased oxygen demand, which might produce myocardial ischemia in someone with significant coronary lesions, he observed. Platelet activation is also increased.

“If the flu can trigger these events in people who are at risk, then it behooves us to do everything we can to minimize the risk associated with influenza,” Solomon said. “Obviously that means vaccination. And we are currently testing a strategy that might provide even better immunity in patients who are at risk.”

Solomon is a principal investigator for the ongoing Influenza Vaccine to Effectively Stop Cardiothoracic Events and Decompensated Heart Failure (INVESTED) trial, which has randomly assigned about 3000 of an estimated target of 9300 patients, he said.

INVESTED is comparing a high-dose trivalent influenza vaccine to a quadrivalent vaccine at a standard dose in patients with a recent history of hospitalization for MI or heart failure and other high-risk features. Mortality and cardiopulmonary hospitalization are the primary endpoints.