Insomnia.... Heart Attack

I thought this was an interesting Norwegian population study from Circulation: Journal of the American Heart Association, Oct 2011. In it, they simply did a chart review of men and women, 52 thousand of them and tried to see if there was an increased amount of heart attacks in those that don't sleep well.

They followed these people over 11.6 years worth of medical charting.
2,368 heart attacks were noted.

They split the population sleep complaints up into three groups:

1. Patients who don't fall asleep quickly (sleep onset insomnia).

2. Patients who don't stay asleep well (sleep maintenance insomnia).

3. And patients who just don't feel subjectively like they got a good night's sleep the next day for no obvious reason they are aware of... (nonrestorative sleep).

And they compared these groups to other patients who had no such sleep complaints in their charts.

1. Those who commonly couldn't fall sleep quickly at the beginning of the night were 45% more likely to have a heart attack than their counterparts without sleep onset insomnia.

2. Those who commonly couldn't stay asleep well were 30% more likely to have a heart attack than their counterparts without sleep mantenance insomnia.

3. Those who complained of nonrestorative sleep the next morning were 27% more likely to have a heart attack than their counterparts who didn't complain of nonrestorative sleep.

Interestingly, while the onset and mantenance insomnia had to be a complaint of almost every night, the nonrestorative complaint only had to be only 2 of 7 nights to see that connection to heart attacks.

That being said, let's point out some weaknesses:
-What sleep problems lead to poor sleep quality and insomnia are not addressed? The problem is likely not only the lack of sleep or quality sleep but perhaps some sleep disorder as a unifying cause of both poor sleep AND heart attacks.
-No sleep studies on any of these patients were done, or at least, not reviewed if done.
-Also, no correlate to timing of the heart attack (nighttime versus early morning versus midday) were made and might have direct relevance.
-Is this Norwegian group relevant to people at lower lattitudes with different risks of heart disease and perhaps a different prevalence of sleep disorders which might interfere with sleep quality?

The likely moral of the story is supported in a growing body of studies:

Not just sleep itself, but quality sleep is needed for your heart and vasculature to "rest" during sleep (your heart never truly "rests") or at least somehow reorient itself biochemically or mechanically for the rigors of the next day. When you don't get sleep or quality sleep, your heart is ALSO paying the price (I would argue ALL organ systems are paying the price in one way or another).

Another VERY IMPORTANT point is that the answer is MOST ASSUREDLY NOT just more sleep medication. In this study, the actual cause of WHY people had insomnia or nonrestorative sleep was not addressed, so masking it with a sleep medication will likely not fix the fact that it's not just sleep, but quality and restorative sleep that is needed.

Sleep medications do not fix a vast majority of the known sleep disorders, and should really be used only to augment therapies for sleep disorders leading to insomnia--- the underlying cause still has to be addressed.

Only about 10% of all patients complaining of insomnia have idiopathic primary insomnia which is an underlying defect in the central nervous system substrate responsible for the sleep-wake cycle and present since birth or early childhood. And only in this small group are sleep agents the first and direct approach to treatment. In those patients, it may reduce heart attack risk, but that would suggest a benefit for the minority of patients.

Below is some of the article in more detail if you would like to read it as well:

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Sleepless Nights May Tax the Heart

A population-based study of more than 52,000 Norwegian men and women suggests that sleepless nights may increase the risk of a heart attack. People who struggled to fall or stay asleep almost every night were 30% to 45% more likely to have an acute MI, Lars E. Laugsand, MD, of the Norwegian University of Science and Technology in Trondheim, and colleagues found. The more insomnia symptoms reported, the higher the risk (P=0.003 for trend), they wrote in Circulation: Journal of the American Heart Association. Although the observation suggests just moderate relative risks, the authors estimated that insomnia may affect as many as one third of adults and symptoms are easily recognizable. "Therefore, evaluation of insomnia might provide additional information in clinical risk assessment that could be useful in cardiovascular prevention," they suggested in the paper. Management can be as simple as following sleep hygiene recommendations, although targeted pharmacological and nonpharmacological therapies may be needed to help with chronic insomnia, the researchers pointed out. They analyzed questionnaire responses from 52,610 men and women living in a single county in Norway and followed for acute MI through national hospital and vital status registries in the Nord-Trøndelag Health Study. During 11.4 years of follow-up, 2,368 incident acute MIs were recorded. Difficulties initiating sleep almost every night were reported at baseline by 3.3% of the participants; trouble maintaining sleep almost every night by 2.5%; and nonrestorative sleep more than once a week by 8.0%. People who struggled to fall asleep almost every night were 45% more likely to have an acute MI (adjusted hazard ratio 1.45, 95% confidence interval 1.18 to 1.80) compared with those who never experienced this sleep problem. Trouble staying asleep nearly every night was associated with 30% elevated risk (adjusted HR 1.30, 95% CI 1.03 to 1.57). Nonrestorative sleep two or more times a week predicted 27% elevated risk of acute MI (adjusted HR 1.27, 95% CI 1.03 to 1.57). These results had been adjusted for age, sex, education, shift work, marital status, depression, anxiety, and heart disease risk factors, such as smoking and physical activity. Sensitivity analyses further excluding the first five years of follow-up, acute MI not hospital verified, and those with chronic somatic disorders didn't have much impact. Potential mechanisms include common risk factors between sleep disorders and heart disease, such as increased sympathetic activation and high blood pressure, they noted. Sleep apnea, which is well-established as a cardiovascular disorder, wasn't assessed. Mgeneralize



Maybe Sleeping Pills aren't all just innocent clouds of blissful sleep...

Can I just tell you that I am slightly frustrated by the fact that I know A LOT about sleep, and not afraid to say it. I studied it exclusively for a year at Duke as a Fellow (after my 4 years of medical school and after my four years of Neurology residency and Neurology certification) to be "Fellowship Trained" in Sleep Medicine and delaying entering the final medical work force by a year just so I could understand sleep that much better. I lecture on it, write articles on it, get consulted about it from fellow physicians.....

AND then my referring docs and patients just want to slap on some wine before bed, or Ambien before bed, or Lunesta before bed, etc. Or they google-read that Dr. Velpo's Magic Supplement (just made that up) will cure their sleep issues.

In they end, they are just masking the real problems... and I care about the real problem, not the sleep. The sleep issue is just a consequence.

95% or more of humanity needs no help sleeping if you treat the underlying problem. Which means 95% or more of the patients I see on one of the hypnotics could come off if we addressed the problem they are trying (and always failing) to mask with the medication.

Okay, stepping off my soapbox, what are the hypnotics:
They are used to make you sleep, whether it be deep enough to cut out an appendix or deep enough to sleep through your husband's snoring.
The list is too long to type here, but I'll mention some of the common ones I see (by their generic names since the drug pharmacy brand names changes from time-to-time):
-Zaleplon
-Zolpidem
-Zopiclone
-Triazolam
-Midazolam
-Temazepam
-Alprazolam
-Alcohol
-Diphenhydramine
-Melatonin
-Ramelteon
-Mirtazapine
-Trazodone
-Risperdone
-Quetiapine
-Olanzapine
-Marijuana

There are MANY reasons to come of these medications if used just for sleep, such as changes in the quality of your sleep with long-term use, change in the sleep stages you get with long-term use, next-day affects on thinking and mood because they change the way your brain tries to rest itself while you sleep, interaction with other medications (usually subtle and under appreciated), unnecessary extra costs, masking the real underlying problem which may be very unhealthy or even deadly if left untreated.... etc.

This study just added to that concern. You can read below the line for more details.

But in summary, they sifted through 10,531 patients from a large U.S. health system who WERE taking a hypnotic (presciption: alcohol, marijuana, etc didn't count) to help them sleep and compared them to 23,674 patients who were NOT taking a hypnotic between the years of 2002 and 2006 to help them sleep. They followed them for 2 and a half years.

Of the people taking sleep agents, 6.1% died.
Of the group not taking anything, 1.2% died.

The more pills one took, the higher their chance of dying.
They even stratified it to amount of use:

HR 3.60 for 0.4 to <18 pills

HR 4.43 for 18 to 132 pills

HR 5.32 for >132 pills

What the above says is that if you take 18 pills a year to help you sleep.... you are 3.6 times more likely to die than if you didn't need the medication.

If you need it more than 18 times but less than 132 times a year, you are 4.43 times more likely to die than if you didn't need the medication.

If you need a sleeping pill more than 132 times a year, you are 5.32 times more likely to die than if you didn't need the medication.

Now, they didn't tell why all these people died, or if the medication was responsible directly (unable to prove) nor how it might be indirectly responsible. This was just a study to note the trend. I think the trend is more trustworthy given the huge numbers of patients involved in the study. The more people in the study, the more the "odd" or "unique" cases become less relevant and even out in the wash.

Take home message: Stop masking the problem. Let's get it straightened out.

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The use of hypnotic sleep aids was associated with a three- to five-fold higher mortality risk compared with the risk for nonusers, even when the prescription was for a small number of pills, investigators reported.

A prescription for 0.4 to 18 doses per year was associated with a mortality hazard ratio of 3.60 compared with patients who had no prescriptions for hypnotics.

The hazard jumped to 5.32 for patients prescribed more than 132 doses a year, investigators reported online in BMJ Open.

"Rough order-of-magnitude estimates ... suggest that in 2010, hypnotics may have been associated with 320,000 to 507,000 excess deaths in the U.S. alone," Daniel F. Kripke, MD, of the Scripps Clinic in La Jolla, Calif., and co-authors wrote. "From this nonrandomized study, we cannot be certain what portion of the mortality associated with hypnotics may have been attributable to these drugs, but the consistency of our estimates across a spectrum of health and disease suggests that the mortality effect of hypnotics was substantial."

Patients who used hypnotics most often also had an increased risk of cancer, with an overall cancer increase of 35% among those prescribed high doses.

More than 30 years ago, investigators in an American Cancer Society-supported study showed that both cigarette smoking and hypnotic use were associated with excess mortality (Arch Gen Psychiatry 1979; 36: 103-116). But the link to hypnotics was largely discounted because the study was not designed primarily to examine these drugs, Kripke and colleagues wrote.

Subsequently, at least two dozen studies examined the mortality risk associated with hypnotic use, and two-thirds of the studies demonstrated significant (P<0.05) associations. Lack of uniformity across the studies precluded a meta-analysis, but 22 of the reports showed a mortality hazard ratio that exceeded 1.0, the authors continued.

Previous studies had several notable limitations, including limited information on the specific types of drugs, confounding with tranquilizers, lack of monitoring of the quantities of drugs provided to patients, and limited data on newer short-acting hypnotics, such as zolpidem, zaleplon, and eszopiclone (Lunesta).

To address some of the limitations of previous work, Kripke and colleagues performed a matched-cohort study based on longitudinal data from a large U.S. health system.

A query of the database identified 10,531 adult patients who had at least one prescription for a hypnotic drug from Jan. 1, 2002 to Sept. 30, 2006. Using the same database, the authors matched the hypnotic-user group with 23,674 patients who did not have a prescription for a hypnotic during the period studied.

Three-fourths of patients prescribed a hypnotic had an explicitly stated sleep-related indication in their records.

Women (mean age 54) accounted for 63.9% of hypnotic users. Hypnotic users and the control group had been followed for about 2.5 years. The users had a mean morbidity score of 1.53. Zolpidem was the most commonly used hypnotic (4,338), followed by temazepam (2,076).

Overall, 6.1% of hypnotic users died during observation, compared with 1.2% of the nonusers. Hypnotic use was associated with a significantly increased mortality risk (P<0.001). The magnitude of the hazard ratio increased with the number of pills prescribed per year (P<0.001 for all comparisons versus nonusers):

HR 3.60 for 0.4 to <18 pills

HR 4.43 for 18 to 132 pills

HR 5.32 for >132 pills

Separate analyses of the two most commonly used hypnotics showed a similar increase in the mortality hazard. For zolpidem the hazard increased from 3.93 for patients who took 5 mg/year to 130 mg/year, to 5.69 for patients who had prescriptions for >800 mg/year (P<0.001).

Patients with temazepam prescriptions totaling 1 mg/year to 240 mg/year had a mortality hazard of 3.71, increasing to 6.56 for >1,640 mg/year (P<0.001).

Overall, only patients whose hypnotic use fell into the top two categories (18 to 132 pills and >132 pills) had an increased cancer risk (HR 1.20, P=0.022; HR 1.35, P<0.001).

For individual drugs, only patients in the top category of zolpidem use had an increased cancer risk (HR 1.28, P=0.023), whereas the two top categories of temazepam use were associated with an increased mortality hazard (HR 1.44, P=0.024; HR 1.99, P<0.001).

The authors acknowledged limitations to this research, most notably that residual confounding could not be fully excluded "due to possible biases affecting which patients were prescribed hypnotics and due to possible imbalances in surveillance."

They also pointed out that cohort studies may demonstrate an association but do not necessarily imply causality. However, "the preferable randomized controlled trial method for assessing hypnotic risks may be impractical due to ethical and funding limitations," they said.

"The meager benefits of hypnotics, as critically reviewed by groups without financial interest, would not justify substantial risks," the authors wrote. "A consensus is developing that cognitive behavioral therapy of chronic insomnia may be more successful than hypnotics.

"Against meager benefits, it is prudent to weigh the evidence of mortality risks from the current study and 24 previous reports, in order to reconsider whether even short-term use of hypnotics, as given qualified approval in National Institute for Clinical Excellence guidance, is sufficiently safe," they added.

Sleepless Mom Increases Risk of Preterm Baby

For us to understand what this study actually communicates to us as the reader, it is helpful to know what scale they used for establishing sleep quality. They used the PSQI (Pittsburgh Sleep Quality Index) which was originally developed in 1989. It tries to cover the broad nature of what makes up sleep quality. It's designed to be able to be filled out by adolescents and above, and is made of 19 self-rated questions (15 scaled questions and 4 fill-in-the-blank). The 15 scaled questions are on a scale of 0 (no difficulty) 3 (severe difficulty) and the 4 fill-in-the-blank are answers to bedtime, wake time, time to fall asleep, how long do you sleep. There are also 5 "bonus" multiple choice questions for the bed partners to rate your sleep quality (keep you honest), which do NOT go into you final score. A number greater than 5 is suggestive of a sleep disturbance of significance. It takes about 5 or so minutes to fill out on average. So, in case YOU want to find out where you stand. I've included the PSQI here for you. 

By the way, this index is NOT designed just for pregnant women but for EVERYONE. This index is NOT designed to tell you WHY you have sleep disruption and DOES NOT predict anything about what an overnight sleep study would show except sleep onset latency (delay) and only sometimes at that.

IF YOU WANT TO COME BACK and fill this out LATER YOU CAN SKIP DOWN to READ MORE ABOUT THE ARTICLE.

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Okay, so this Index is for ANYONE, but if you are a woman who is pregnant, plan to be pregnant, or have have pity for pregnant women, then this index and this study is applicable.

In it, they followed 166 pregnant women.

Average age was just over 28.

They used the above sleep quality scale to judge what the quality of their sleep was (but, again, not necessarily WHY their sleep wasn't great), and then decided if there was a link to them having preterm babies.

What's a preterm baby? A baby born after less than 37 weeks. So, as they note, preterm babies are on the rise in America. Over the last 25 years, the rate has increased by 3% (from 9 to 12% over that time). No one is sure exactly why it seems to be increasing.

So they looked at how well moms slept at 14-16 weeks, 24-26 weeks, and 30-32 weeks using this score and how that related to preterm baby risk.

Findings:

If you can't sleep well during the first range (14-16 weeks) then you are 25% more likely to have a preterm baby than the mom who slept well.

If you can't sleep well during the third range (30-32 weeks) then you are 18% more likely to have a preterm baby, which is a more modest increase.

What about that middle 24-26 week range? Those mom's slept better and there was no significant increase in preterm risk, and it's well-established that moms just sleep better during that time anyway for some hormonal reason we don't really understand well enough yet.

WHY DOES THIS CAUSE A GREATER PRETERM RISK? Not sure. The working hypothesis that needs more testing is that the increase inflammatory mediators released by the stress of not sleeping well (or by the same stress that causes one not to sleep) induces a cascade leading an early delivery. 

What the study didn't questionaire for was such things as chronic pain/financial stress/life-event stress/relationship stress/post-traumatic stress disorders, etc. in enough numbers and ways to connect these things as a cause for poor sleep and therefore preterm delivery, although a future test may help make this connection more fully now that this current study sets a precendent for future studies involving more pregnant, sleepy women willing to fill out longer questionnaires. 

A LONGER VERSION OF THE STUDY IS HERE BELOW IF YOU WANT TO READ IT...

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Mom's Poor Sleep Linked to Preterm Birth

Okun ML, et al. "Poor sleep quality is associated with preterm birth" Sleep 2011; DOI: 10.5665/sleep.1384.

Poor sleep quality, in both early and late pregnancy, may be associated with an increased risk of a preterm delivery, researchers said.

Poor sleep quality was a predictor of preterm birth in early pregnancy (14-16 weeks), and with every one-point increase on a sleep index scale, the odds of preterm birth increased 25%, reported Michele L. Okun, PhD, of the University of Pittsburgh, and colleagues in the November 1 issue of Sleep. The odds increased by 18% in later pregnancy, they said.

Although the specific pathways through which disturbed sleep contributes to preterm birth are unknown, it is possible that poor sleep may act independently or with other established risk factors, such as stress, they wrote.

The rate of preterm birth in the U.S. has increased from approximately 9% to 12% in the last 25 years. Poor sleep quality during pregnancy is related to adverse health outcomes.
Previous research has evaluated whether sleep quality during pregnancy is a clinically relevant risk factor for preeclampsia, longer labor, poor delivery outcomes, postpartum depression, and preterm birth. Although several risk factors have been identified, a gap in understanding the pathophysiology of preterm birth remains, the authors stated.
Okun's group evaluated the relationship between subjective sleep quality at 14-16, 24-26, and 30-32 weeks gestation and the risk of preterm delivery (<37 weeks). They hypothesized that poor sleep quality, especially in early pregnancy, is associated with an increased risk of delivering preterm.

In addition, the researchers explored the possibility that disrupted sleep might partially explain the established relationship between psychosocial stress and preterm birth.
Participants in the study included 166 pregnant women (mean age 28.6). Self-report questionnaires, including the Pittsburgh Sleep Quality Index, were used. Logistic regression models were used to evaluate whether sleep quality was linked to preterm delivery.
They found that poor sleep quality was a predictor of preterm birth, with the largest effects, a 25% increase, in early pregnancy at 14-16 weeks (OR 1.25, 95% CI 1.04-1.50, P=0.02).
More modest effects (18%) were found in later pregnancy at 30-32 weeks (OR, 1.18, CI 0.98-1.42, P=0.07).
Sleep quality in the second trimester did not correlate with increased risk and the authors suggested sleep often improves modestly during this part of pregnancy, although it was not unclear why. One explanation might be hormones or other biological pathways playing a role, but there are no data on that theory, they added.

However, the data from this study provide new evidence to support the hypothesis that disturbed sleep in early pregnancy may become a critical risk factor for adverse pregnancy outcomes.
Okun and her co-authors suggest a biological cause for this relationship: Poor sleep quality has been shown to initiate inflammation, possibly activating the processes associated with premature childbirth. Sleep disruption also might do this in combination with stress, a known activator of inflammation.
Other influences on impaired sleep included financial stress, stressful life events, and post-traumatic stress disorder.

Study limitations included the small size of the study and the inability to generalize to all women. Also, although sleep quality was the only measure of sleep available, additional measures, such as continuity and duration, are needed to provide supporting evidence, the researchers said. Further studies are need to test the relationship, they said.
What is unique in this study, Okun said, is that it may be possible to identify a risk early in the pregnancy, when there is time to intervene, possibly with modifications in behavior.