ACCEL: Interviews and Topical Summaries of Cardiology’s Most Interesting Research Areas

CardioSource WorldNews | Calculating Who Will (and Won’t) Benefit from DAPT

Recently, we have seen a new systematic review of the use of dual antiplatelet therapy (DAPT)1 and the recent update of the ACC/American Heart Association (AHA) guidelines on duration of DAPT in patients with coronary artery disease (CAD).2

The DAPT study demonstrated that the risks of MI and stent thrombosis (ST) beyond 1 year after PCI were reduced by continued thienopyridine therapy (clopidogrel or prasugrel) plus aspirin compared to placebo plus aspirin at 12 months. That’s the good news; as you can imagine, the beneficial effects of being randomized to 18 months of continued DAPT after 12 months of such therapy came at the cost of higher moderate and severe bleeding than being rerandomized to placebo and aspirin for the same period of time. Moreover, there was a nominal signal suggesting increased all-cause mortality with continued DAPT. (See the May issue of ACCEL for more details.)

All of this was important to know, of course, but the relative benefit and risk was not well-defined. Specifically, in trying to balance risk versus benefit from continued DAPT, how did a history of MI prior to stent treatment affect this risk/benefit analysis? And was there any additional utility to using a decision tool (DAPT Score) to better gauge benefit versus risk? Those issues were at the heart of a new analysis of the DAPT study.

A Tool to Individualize Therapy

Recently, Robert W. Yeh, MD, FACC, and colleagues published a paper in JACC presenting a clinical decision tool to identify patients expected to derive benefit versus harm from continuing thienopyridine (clopidogrel or prasugrel) therapy beyond 1 year post-PCI.3 Dr. Yeh is an interventional cardiologist and director of the new Center for Outcomes Research in Cardiology at Beth Israel Deaconess Medical Center, Boston, MA.

The tool was based on stratification of patients participating in the DAPT study and was validated on patients in the PROTECT (Patient-Related Outcomes with Endeavor versus Cypher Stenting) trial.

You can see the DAPT Score detailed in the TABLE. Overall, lower DAPT scores were associated with higher bleeding risk (with or without continued thienopyridine therapy) and less ischemic benefit from treatment while higher DAPT scores were associated with lower bleeding risk and larger absolute ischemic benefit.

The 25,682 patients enrolled in the DAPT study were categorized according to any history of MI prior to the index procedure or no history of MI. Risk differences during the randomized treatment period (12–30 months) for ischemic (MI and/or ST) and bleeding (GUSTO moderate/severe) events were compared according to DAPT score. Rates of MI were 3.8% vs. 2.4% (p = 0.01) for patients with any MI versus no MI.

Continued thienopyridine reduced late MI compared with placebo regardless of MI history (HR: 0.46; p < 0.001 any MI; HR: 0.60; p = 0.003 no MI) and increased bleeding (HR: 1.86; p = 0.01 any MI; 1.58; p = 0.01 no MI). DAPT scores ≥ 2 were associated with reductions in MI/ST with continued thienopyridine versus placebo (2.7% vs. 6.0%; p < 0.001 any MI; 2.6% vs. 5.2%; p = 0.002 no MI), with bleeding rates of 1.5% vs. 1.1% (p = 0.24) and 2.2% vs. 2.0% (p = 0.68), respectively.

Among patients with DAPT scores < 2, in both groups, continued thienopyridine was associated with increased bleeding (3.2% vs. 1.2%, p = 0.01 any MI; 2.9% vs. 1.6%, p = 0.004 no MI), and ischemic rates of 2.1% vs. 3.2% (p = 0.17) for patients with previous MI and 1.5% vs. 2.0% (p = 0.21) for those without.

Not Easy (but Clearer)

Where are we then? Optimizing therapy for individual patients in order to minimize these counterbalancing risks is complex and not simply determined by MI status. Indeed, in the study by Yeh and colleagues, although patients with any MI (versus no MI) derived greater absolute reductions in risk for MI/ST, the relative hazards for major bleeding events were similar (HR: 1.86; p = 0.01 any MI; HR: 1.58; p = 0.01 no MI).

Of note, the DAPT score included a history of MI; by definition, patients with any MI would be expected to have higher scores. Nonetheless, the score still differentiated between those who would benefit from or be harmed by continuation of thienopyridines among patients within each of these groups. Note that 35% of the no MI cohort had high DAPT scores, which would predict ischemic benefit exceeding bleeding risk; on the other hand, 30% of the any MI cohort had low DAPT scores which would predict bleeding risk exceeding ischemic benefit.

Thus, almost one-third of the patients in either MI subgroup (any or no) might have been more accurately prescribed risk appropriate duration of dual antiplatelet therapy based on DAPT score compared with MI status alone.

Based on this study, here’s what you need to know: among patients with MI eligible for prolonged thienopyridine therapy at 1-year post-PCI, the DAPT Score appears to provide a more accurate benefit versus risk assessment upon which individualized thienopyridine therapy may be appropriately prescribed. A high DAPT score (≥ 2) predicts ischemic benefit without incremental bleeding risk with extended thienopyridine therapy beyond 1 year. (Keep a copy of the TABLE handy so you can calculate the DAPT score. Or you can use an online calculator, available at the DAPT study website:


  1. Bittl JA, Baber U, Bradley SM, et al. J Am Coll Cardiol. 2016;doi:10.1016/j.jacc.2016.03.512
  2. Levine GN, Bates ER, Bittl JA, et al. J Am Coll Cardiol. 2016; doi:10.1016/j.jacc.2016.03.513
  3. Kereiakes DJ, Yeh RW, Massaro JM, et al. J Am Coll Cardiol. 2016 doi:10.1016/j.jacc.2016.03.485

PCI vs. OMT for Stable IHD: What Part of the Term
‘Optimal Medical Therapy’ Is Confusing?

There have been several trials in the contemporary era comparing percutaneous coronary intervention (PCI) versus optimal medical therapy (OMT) for treating patients with stable ischemic heart disease (SIHD), such as COURAGE, BARI 2D, FAME 2, and ISCHEMIA. None of these trial have shown a clear reduction in death or MI with PCI, not even in patients with diabetes (BARI 2D). Long-term follow-up did not make a difference; in FAME 2, for example, there was still no difference in death or MI at 2 years of follow-up, nor at 5 years in BARI 2D or even at up to 15 years in COURAGE.1 The latter is notable given that at 4.6 years, there was a trend in the COURAGE study suggesting better survival with PCI versus OMT.

FAME 2 evaluated fractional flow reserve (FFR)-guided PCI for SIHD and while there were no significant between-group differences in the rates of death and MI, landmark analysis indicated that the rate of death or MI from 8 days to 2 years was lower in the PCI group than in OMT group (4.6% vs. 8.0%; p = 0.04), although it should be noted that only a small number of patients achieved that duration of follow-up.

William E. Boden, MD, FACC, professor of medicine, Albany Medical College, and chief of medicine, Albany Stratton VA Medical Center, New York, NY, was the lead investigator of the COURAGE trial.2 He noted that FAME 2 randomized patients after catheterization; physicians treating patients in the OMT arm knew the anatomy and FFR results. Dr. Boden explained that if the primary endpoint of COURAGE and BARI 2D included revascularization procedures, there would have been a significant difference between the arms. Also, he pointed out that success of OMT/risk factor control in FAME 2 has not been reported.

So, is there any high-risk group of SIHD patients in whom revascularization improves death/MI in the era of contemporary OMT that includes intensive lifestyle intervention and aggressive, multifaceted secondary prevention?

OMT Rocks (And Still Underutilized)

What about significant multivessel angiographic coronary artery disease (CAD) and/or a proximal left anterior descending (LAD) stenosis? In an evaluation of COURAGE patients,2 PCI and proximal LAD stenosis did not influence any outcome. Death was predicted by low LVEF (HR: 1.86; p < 0.001) and the number of diseased vessels (HR: 1.45; p < 0.001). MI and non-ST-segment elevation (NSTE) ACS were predicted only by the number of diseased vessels (HR: 1.53 for MI and 1.24 for NSTE-ACS; p = 0.007).

Dr. Boden noted that if you look at the broad swath of available data, comprising 16 RCTs in 8,820 patients (including diabetics with multivessel disease), there were no reductions in death, MI, stroke, or other “hard events” with PCI in the modern era of contemporary OMT. Having said that, he quickly added that OMT remains under-utilized in patients undergoing revascularization.

In a recent editorial comment in JACC,3 Dr. Boden (and David J. Maron, MD, FACC) wrote that the data supporting OMT “are compelling and argue persuasively that all patients with SIHD should receive OMT, regardless of whether they undergo revascularization. However, the use of OMT remains disappointingly low in patients with SIHD.”

The commentary was discussing findings of Bittner et al.4 who, in the same issue of JACC, provided powerful evidence that simultaneous control of multiple risk factors improves survival and reduces nonfatal MI and stroke. “For that singular reason,” Boden and Maron wrote, “OMT needs to be more widely embraced and utilized by clinicians as both a best medical practice and a universal standard of care in all patients with coronary artery disease.”


  1. Sedlis SP, Hartigan PM, Teo KK, et al. N Engl J Med. 2015;373:1937-46.
  2. Mancini GB, Hartigan PM, Bates ER, et al. Am Heart J. 2013;166:481-7.
  3. Maron DJ, Boden WE. J Am Coll Cardiol. 2015;66:774-6.
  4. Bittner V, Bertolet M, Barraza Felix R, et al. J Am Coll Cardiol. 2015;66:765-73.

Disturbed Sleep, Aging and CVD
Why sleep is a big CV risk factor

More than 70% of patients with heart failure (HF) report poor sleep and 50% report insomnia symptoms, including difficulty initiating sleep, maintaining sleep, or awakening too early in the morning. This is of concern because insomnia is associated with daytime symptoms and negative functional and quality of life (QOL) outcomes among HF patients who suffer disproportionately from these concerns.

One of the biggest issues—seen broadly in patients with cardiovascular disease (CVD), not just those with advanced disease—is sleep-disordered breathing (SDB), such as sleep apnea. In one study of 170 patients, full polysomnography testing demonstrated that 51% of patients with stable chronic HF had SDB.1

That might be a surprise to you, since patients freely admit they are not sharing such information with you. Nancy S. Redeker, PhD, RN, a professor at Yale School of Nursing, and her colleagues, who conducted that study on the prevalence of SDB in the setting of stable HF, have shown that patients use a variety of strategies to manage their insomnia, but generally do not mention their sleep concerns to physicians “whom they perceived as not interested in sleep.”2 In short, from the patient’s perspective: “Docs don’t ask, we don’t tell.”

Why should you be interested in sleep problems?

Like SDB, both poor sleep quality and insomnia have negative consequences in patients (TABLE) that could drive CVD. For example, sleep quality and insomnia are associated with poor physical function, shorter 6MWD, fatigue/malaise, mood disturbance/irritability, and proneness to errors and accidents. Individuals with insomnia are five times more likely to be depressed than those without insomnia. Not surprisingly, sleep disturbances are associated with poor medication adherence.

To Sleep, Perchance to DREAM Study

Importantly, it’s not just a QOL issue; there is a strong link between insomnia and hypertension (a three- to five-fold increased risk depending on the hours of sleep achieved. There also appears to be a strong dose-dependent association between the number of insomnia symptoms and acute MI as well as HF risk. It’s not just in older patients, either. In one study of active military service members, insomnia was associated with a two-fold increased risk of diabetes.3 (This was an analysis of the Defense Medical Surveillance System, which identified more than 200,000 incident cases of chronic insomnia.)

What happens during sleep can be a big health issue, too. Redeker and colleagues recently reported the results of a cross-sectional analysis of 697 veterans who underwent polysomnography for suspected SDB. The DREAM (Determining Risk of Vascular Events by Apnea Monitoring) study showed that patients with moderate-severe SDB had almost three-fold greater unadjusted odds of any cardiac arrhythmia compared to those without SDB (2.94; 95% CI: 2.01 to 4.30; p = < 0.0001).4 They also had two-fold greater odds of tachyarrhythmias (2.16; 95% CI: 1.47–3.18; p = 0.0011), two-fold greater odds of complex ventricular ectopy (2.01; 95% CI: 1.36–2.96; p = 0.003), and two-fold greater odds of intraventricular conduction delay (2.50; 95% CI: 1.58–3.95; p = 0.001).

A linear trend also was identified between SDB severity and all cardiac arrhythmia subtypes (p value linear trend < 0.0001). After adjusting for age, body mass index, sex, and CVD, moderate-severe SDB patients still had twice the odds of nocturnal cardiac arrhythmias (2.24; 95% CI: 1.48–3.39; p = 0.004). Frequency of obstructive respiratory events and hypoxia were strong predictors of arrhythmia risk.

In brief: sleep-disordered breathing is independently associated with nocturnal cardiac arrhythmias and as the severity of SDB increases, so too does the risk for any cardiac arrhythmia

This is just part of what we’ll eventually learn from DREAM, which has a total study population of 1,840 predominantly male, middle-aged veterans.5

Until we learn more, what can be done now? As Dr. Redeker’s research has shown, patients want relief from insomnia, but they rarely if ever mention this concern to physicians, whom they perceive as “just taking your blood and giving you another pill.” They want their physicians to ask “how they are sleeping,” and are interested in educational and behavioral strategies to help them sleep and would be willing to “try anything,” especially if it decreased their dependence on sleep medications.

The good news is Dr. Redeker’s work suggests that cognitive behavioral therapy for insomnia seems to reduce these risks we’ve been talking about.6 In a pilot study published in 2015, cognitive behavioral therapy was feasible, acceptable to patients, and had a statistically significant effect on insomnia and fatigue, while controlling for the effects of comorbidity and age.

Even before they conducted this pilot, patients expressed an interest in this kind of an approach. When asked about their potential interest in behavioral sleep treatment, one participant stated: “I’d eat a bucket of nails if it you told me it would help me sleep.”2

(Note: Two more reasons you might want to access the July 2016 edition of ACCEL: Virend K. Somers, MD, PhD, FACC, discusses obstructive sleep apnea and cardiovascular disease and Arshad Jahangir, MD, PhD, FACC, spends quality time addressing restless legs syndrome and its effect on cardiac structure, function and outcomes.)


  1. Redeker NS, Muench U, Zucker MJ, et al. Sleep. 2010;33:551-60.
  2. Andrews LK, Coviello J, Hurley E, et al. Heart Lung. 2013;42:339-45.
  3. Lewis PE, Emasealu OV, Rohrbeck P, et al. MSMR. 2014;21:6-13.
  4. Selim BJ, Koo BB, Qin L, et al. J Clin Sleep Med. 2016 [Epub ahead of print].
  5. Koo BB, Won C, Selim BJ, et al. Sleep Breath. 2016;20:893-900.
  6. Redeker NS, Jeon S, Andrews L, et al.
  7. J Clin Sleep Med. 2015;11:1109-19.
Read the full July issue of CardioSource WorldNews at

Clinical Topics: Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure, Interventions and Coronary Artery Disease

Keywords: American Heart Association, Coronary Artery Disease, Diabetes Mellitus, Heart Failure, Myocardial Ischemia, Percutaneous Coronary Intervention, Sleep Initiation and Maintenance Disorders, CardioSource WorldNews

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