You don't need to be signed in to read BMJ Blogs, but you can register here to receive updates about other BMJ products and services via our site.

Cardiol – CAD

Primary Care Corner with Geoffrey Modest MD: Cardiovascular Fitness — a new vital sign?

19 Jan, 17 | by EBM

By Dr. Geoffrey Modest

A recent scientific statement from the American Heart Association stresses the importance of assessing cardiorespiratory fitness (CRF) as part of the risk assessment for cardiovascular disease (see DOI: 10.1161/CIR.0000000000000461)​.

Details:

  • Studies since the 1950s have consistently found that CRF is a strong and independent marker of cardiovascular risk as well as all-cause mortality, adjusting for age and the other standard risk factors. This is been found in healthy men and women, those with known or suspected cardiovascular disease, and those with the co-morbidities of obesity, type 2 diabetes, hypertension, and hyperlipidemia. In many studies CRF is a more powerful predictor of mortality risk than traditional cardiovascular risk factors. It has even been shown to be a more powerful risk predictor than ST-segment depression, cardiovascular symptoms, or hemodynamic responses.
  • The survival benefit in 13 studies showed that each 1-MET (metabolic equivalent) higher CRF, a small increment, was associated with a marked 10-25% improvement in survival. And, one study found that men who improved from unfit to fit between two successive examinations had a reduction in mortality risk of 44% relative to those who remained unfit in both exams (i.e., those with higher CRF have dramatic clinical benefit)
  • As a quick guide to METs:
    • Light activity (<3 METs): includes walking 2.5 mph (2.9 METs)
    • Moderate activity (3-6 METS): includes walking 3.0 mph (3.3 METs), walking 3.4 mph (3.6 METs), stationary biking (light effort) 5.5 METs
    • Vigorous activity (>6 METs):  jogging (7.0 METs), calisthenics/pushups/situps (8.0 METs), rope jumping (10.0 METs)
  • Of note, even though the most dramatic differences in all-cause and cardiovascular mortality were found comparing the most fit to the least fit subjects (70% and 56% respectively), the greatest increase in mortality benefit was in comparing the least fit group to the next least fit category
  • A recommendation in the paper is that CRF should become an accepted “vital sign”, and should be part of the standard clinical encounter
  • CRF also is associated with heart failure exacerbations and mortality, with one study finding that for every 6% increase in CRF over three months there was a 4% lower risk of cardiovascular mortality or hospitalization, and an 8% decrease risk of cardiovascular mortality or heart failure hospitalization (for example, see http://blogs.bmj.com/ebm/2016/11/09/primary-care-corner-with-geoffrey-modest-md-vigorous-exercise-helps-those-with-heart-failure/ which shows the benefit of vigorous exercise in patients with heart failure and reduced ejection fraction), timing of cardiac transplantation, preoperative surgical risk prediction (including studies of abdominal aortic aneurysm repair, liver transplant, lung cancer resection, upper GI surgery, intra-abdominal surgery, bariatric surgery, coronary artery bypass grafting). And interventions seem to help: in patients waiting for CABG surgery, those randomized into an exercise training group had superior outcomes to the control group, with a reduced rate of perioperative complications and shorter hospital stays. And observational studies have also shown that men with higher CRF had 68% lower stroke mortality, controlling for standard risk factors.
  • There were a few studies showing that those with a higher level of CRF had a reduced risk of developing dementia or Alzheimer’s, one study showing a 36% lower risk of developing dementia in those with the highest quartile of CRF. Higher levels of CRF are also associated with lower measures of anxiety or depression symptoms
  • Many studies have shown decreased risk of development of prediabetes, metabolic syndrome, and type 2 diabetes in those with higher CRF, again with the biggest difference in those going from lower CRF to the moderate range.
  • Lower levels of CRF at a younger age are also associated with a higher risk of disability at an older age. For example one study of obese adults with type 2 diabetes found that after four years, improvement of CRF decrease the likelihood of developing disability
  • Added value of CRF to the traditional risk calculators:
    • Several analyses have looked at various ways of incorporating the additional value of CRF. In one 30-year study of patients with stage II hypertension, the 30 year risk of cardiovascular mortality was 18.4% in those with low CRF versus 10.1 present in those with high CRF (i.e., a huge difference)
    • Overall, adding CRF to the traditional risk stratification led to actual CVD and all-cause mortality outcomes being correctly reclassified through the risk predictor as being decreased 23.3% and 20.6% respectively through correctly reclassifying patients as higher risk, and 55.8% and 46.0% respectively for correctly reclassifying patients as lower risk. The overall changes reflected a 30.5% and 24.5% correct reclassification for all-cause mortality, with larger changes in correctly reclassifying patients as lower risk because of CRF. [e., those at apparently high risk by a traditional risk calculator, in reality have significantly lower risk if they are more fit; there are changes apparent in the other direction as well, but less emphatically so]. Also as a point of comparison, when looking at the nontraditional risk factors, such as coronary artery calcium scores  (which seems to be the best of the lot), the level of correct reclassification from the traditional risk calculators is much lower
  • So, how does one measure CRF?
    • The most accurate and standardized quantification of CRF is through CPX (cardiopulmonary exercise testing), a combination of conventional exercise testing with ventilatory expired gas analysis
    • A step below that is to look at achieved treadmill speed/grade and duration, making sure the patient does not hold the hand rails
    • Another approach is to look at submaximal exercise testing or the 6-minute walk test to assess distance walked (walking <350 meters is associated with high risk).
    • And the easiest overall/least time-consuming/cheapest/easiest to implement is to do nonexercise prediction calculations. These are not standardized at this point, and each study seems to have somewhat different calculators. Perhaps the best is to use the one by Nes BM. Med Sci Sports Exerc 2011; 43: 2024, which incorporated an assessment of patient reported physical activity, age, waist circumference, and resting heart rate, and this is one of the studies which included a lot of people (n= 2067 men and 2193 women) and looked at actual clinical outcomes, finding that 90.2% of women and 92.5% of men in the lowest two quartiles of fitness were correctly classified. Their questions for physical activity included: frequency of exercise (never, <1x/wk, 1x/wk, 2-3x/wk, >3x/wk), intensity (“no sweat/heavy breathing, “heavy breath and sweat”, “push myself to exhaustion”), and duration (<15 in, 15-30 min, 30-60 min, >60 min).
    • Overall exercise recommendations:
      • Type: exercise should involve major muscle groups (legs, arms, trunk) that is continuous and rhythmic (e.g. brisk walking, jogging, cycling, swimming, rowing)
      • Intensity: moderate and/or vigorous intensity relative to the persons capacity
      • Frequency: at least five days per week of moderate or three days per week of vigorous intensity exercise
      • Time: 30 to 60 minutes per day (150 minutes per week) of moderate and 20 to 60 minutes per day (75 minutes per week) of vigorous exercise. Of note between 10 and 20 minutes can be beneficial in previously inactive people
      • Amount: a target of 500 to 1000 MET-min/wk
      • Pattern: one continuous session per day or multiple sessions per day of greater than 10 minutes each. Less than 10 minutes may work in deconditioned individuals.

Commentary:

  • Incorporating CRF reflects a more individualized physiologic approach (assessing the constellation of how well the heart, lung, circulation, and oxygen extraction by muscles works). It is clear from epidemiologic data that on a community basis, as well as individual basis, the traditional risk factors of smoking, hypertension, hyperlipidemia, and diabetes confer an increased risk of cardiovascular disease. However, CRF is a truly specific individual physiologic risk factor, reflecting how these risk factors and more play out in the individual’s body. For example, hypertension itself confers different levels of individual risk dependent on CRF.
  • One note of caution: there is no uniformity in clinical practice as to which of the traditional risk calculators is the best: the Am Heart Association/Am College of Cardiology just published an updated tool, including a spreadsheet calculator (see org/10.1161/CIR.0000000000000467 for the article, and http://circ.ahajournals.org/highwire/filestream/234917/field_highwire_adjunct_files/0/Appendix_Users_Guide_Spreadsheet.xlsfor the spreadsheet to calculate risk. BUT, this tool also needs to be validated in different populations prior to being accepted (also, see http://blogs.bmj.com/ebm/2015/08/05/primary-care-corner-with-geoffrey-modest-md-comparison-of-the-2013-accaha-lipid-guidelines-to-atpiii/ for a critique of the 2013 ACC/AHA lipid guidelines.)
  • Interestingly, several studies suggest that CRF is a more potent predictor of cardiovascular disease than any of the individual risk factors we have incorporated into our predictive models
  • Why is CRF so important? There are several explanations: improved traditional cardiovascular risk profiles (though most of the studies did control for the major ones we know), changes in autonomic tone that may reduce arrhythmogenic risk, fewer thrombotic events (exercise decreases fibrinogen levels, for example), improved endothelial function, lower levels of visceral adiposity/improved insulin sensitivity, lower levels of inflammation, as well as perhaps improved mental health and sense of well-being. And, there might be important positive changes in the gut microbiome with exercise, which is clear in animal models, less clear in humans where those who exercise tend to eat differently from those who do not, so hard to control well).
  • I should add a couple of caveats here: it is important not to confound fitness with doing lots of exercise; a significant component of fitness (on the order of 30+%) is genetic and not related to regular exercise. And most of the studies above are observational, not intervention studies (i.e., only a few actually randomized patients to exercise programs vs none and looked at long-term outcomes. Though the one on pre-surgery exercise programs was pretty impressive. And, the overall data on the benefits of exercise overall are quite robust)
  • For ballpark figures, those with a CRF level less than 5 METs have a particularly high risk of mortality, whereas those with CRF levels of greater than 8 to 10 METS seem to have much more protection. And, more than half the reduction in all-cause mortality occurs between those who are least fit (e.g. CRF less than 5 METs) and those in the next least fit group (e.g. CRF 5-7METS); i.e., benefits for cardiorespiratory fitness are particularly strong in those people in the least fit as compared to the next higher category (i.e., one does not need to be an Olympic athlete to achieve the benefits)

So, the key points here are:

  • Cardiorespiratory fitness is an independent in additive risk assessor for total and cardiovascular mortality
  • Improving CRF dramatically decreases cardiovascular and all-cause mortality
  • This clinical improvement is especially profound in those who are the least fit, finding a greater than 50% risk reduction by moving one step up to the next least fit group. An increase in CRF of only one MET is associated with the 10 to 20% decrease in mortality rate
  • There is a reasonable argument based on studies that have been done to propose that a simple, non-exercise based calculator should be added as a vital sign. This could easily be measured by nonclinical staff and would provide clinicians important information to help encourage patient-specific exercise programs. This should to be evaluated more completely in different populations to assess its generalizability. However, even without those studies, given the documented benefits of exercise and the dramatic relationship in the above studies of CRF as a risk predictor, I personally will ask patients about CRF more and further reinforce the importance of exercise as part of a healthy lifestyle.

For other blogs on exercise, see http://blogs.bmj.com/ebm/category/exercise/

Primary Care Corner with Geoffrey Modest MD: FDA broadens indication for empagliflozin to include cardiovascular protection!!!

8 Dec, 16 | by EBM

By Dr. Geoffrey Modest

The FDA just extended the indication for the diabetes drug empagliflozin (Jardiance) to include reducing cardiovascular mortality in those with diabetes and cardiovascular disease. Their press release (see http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm ) states that they looked at postmarketing data, though their original approval 2 years ago indicated that they requested 5 years of post-marketing data.

See my prior blog critiquing the original study leading to FDA approval ( http://blogs.bmj.com/ebm/2015/12/21/primary-care-corner-with-geoffrey-modest-md-empaglifozin-the-good-and-the-bad/ )

Primary Care Corner with Geoffrey Modest MD: Prediabetes and cardiovascular risk: a lower cutpoint?

5 Dec, 16 | by EBM

By Dr. Geoffrey Modest

A recent systematic review/meta-analysis assessed the association between prediabetes by different definitions and all-cause/cardiovascular mortality (see doi.org/10.1136/bmj.i5953)

Details:

  • 53 prospective cohort studies with 1,611,339 individuals were followed a median of 9.5 years.
  • The researchers assessed different criteria for defining glucose intolerance:
    • Impaired fasting glucose
      • IFG – ADA (American Diabetes Association): 100 to 126 mg/dL
      • IFG – WHO (World Health Organization): 110 to 126 mg/dL
    • Impaired glucose tolerance: 140 to 200 mg/dL, which is consistent across guidelines, based on 2-hour plasma glucose during an oral glucose tolerance test
    • Raised hemoglobin A1c:
      • ADA: 5.7 to 6.4%
      • NICE guidelines (UK): 6.0-6.4%
    • They specifically looked for the following endpoints: composite cardiovascular events (combination of coronary heart disease, stroke, or “other type of cardiovascular disease”), coronary heart disease, stroke, and all-cause mortality.

Results:

  • As compared to normoglycemia (only statistically significant associations are reported below),
    • Risk for composite cardiovascular disease was increased 13% for IFG – ADA, 26% for IFG– WHO and 30% for impaired glucose tolerance
    • Risk for coronary heart disease was increased 10% for IFG – ADA, 18% for IFG– WHO, and 20% for impaired glucose tolerance
    • Risk of stroke was increased 6% for IFG– ADA, 17% IFG– WHO, and 20% for impaired glucose tolerance
    • All cause mortality was increased 13% for IFG– ADA, 13% for IFG– WHO, and 32% for impaired glucose tolerance
    • Note: the observed increased risk occurred with fasting glucose as low as 100 mg/dL
  • In terms of A1c:
    • Those in the 5.7 to 6.4% range had an increase of the composite cardiovascular disease of 25% and coronary heart disease 28%
    • Note: they found that the risk of composite cardiovascular events and coronary heart disease were higher in people with an A1c in the 5.7 – 6.4% vs. the 6.1 – 6.4% group (i.e., the lower numbers mattered)

Commentary:

  • Overall, the study found that there was an increased risk of cardiovascular disease and all-cause mortality with fasting glucose as low as 100 mg/dL or a hemoglobin A1c of 5.7%. So, they strongly support the ADA definitions of prediabetes, which have not been accepted at this point by the European Society of Cardiology, the European Association for the Study of Diabetes, or the European Diabetes Epidemiology Group.
  • This review is useful given that individual published studies have found mixed results on the actual cutpoint of impaired fasting glucose associated with increased cardiovascular disease.
  • However, this study did not have data on the future development of diabetes during the follow-up period, and other data suggest that diabetes increases cardiovasc outcomes more than prediabetes
  • They did find that the risk of all-cause mortality was actually significant higher in the impaired glucose tolerance group than in the groups with other definitions of prediabetes, suggesting that impaired glucose tolerance may be a stronger risk factor for all-cause mortalitythan other definitions of prediabetes, though not for cardiovascular disease
  • Other studies have suggested that impaired glucose tolerance is associated with increased risk of cancer mortality in Australia as well as in Mauritius
  • Of considerable importance is that the more aggressive definition by the ADA includes lots more people, 36.2% of those in the US and 50.1% in China, for example. i.e., this is a huge public health issue
  • The ADA does now recommend considering pharmacologic therapy in patients with impaired glucose tolerance and impaired fasting glucose as well as at least one of: age <60, BMI >35, family history of diabetes in first-degree relative, high triglycerides, decreased HDL, hypertension, and hemoglobin A1c >6.1%

So, the main reason I bring up this issue is to make sure we’re all aware of the significant increase in cardiovascular and all-cause mortality associated with glucose intolerance, even at the remarkably common A1c level of 5.7% (and this raises the issue of what the lower limit really is, in terms of cardiovascular outcomes. And, about 80% of diabetics die ultimately die from CVD, even though those with this level of A1c only very slowly progresses to diabetes, if at all). Basically, I do think it is really important for us to aggressively pursue nonpharmacologic therapies to decrease both the glucose intolerance and these adverse consequences. In addition, I think the increased risk for cardiovascular disease at lower levels of glucose intolerance should be factored into our overall preventive strategies around atherosclerotic disease, including not just more aggressive nonpharmacologic therapies (e.g., strongly reinforcing managing the other cardiovascular risk factors, BMI, etc., esp. through diet, exercise….), but also perhaps an earlier initiation of statins and perhaps aspirin.

Primary Care Corner with Geoffrey Modest MD: Lifestyle Changes and Genetic Risk for CAD

17 Nov, 16 | by EBM

By Dr. Geoffrey Modest

A recent study looked at the relative effects of genetic risk and healthy lifestyle in the development of coronary artery disease (see DOI: 10.1056/NEJMoa1605086).

Details:

  • 3 prospective cohorts were followed: the Atherosclerosis Risk In Communities (ARIC, with 7814 white people between the ages of 45 and 64), the Woman’s Genome Health Study (WGHS, with 21222 white female health professionals), and the Malmo Diet and Cancer Study (MDCS, with 22389 Swedish people aged 44 to 73 and free from prevalent cardiac disease). Also included were 4260 people the cross-sectional BioImage Study who had genetic/risk factor data and had coronary artery calcium (CAC) scores
  • They evaluated these people for up to 50 single–nucleotide polymorphisms (SNPs) known to be associated with coronary artery disease, and then derived a polygenic risk score based on the number of risk alleles at each SNP, multiplied by the sum of the literature-based clinical effect size.
  • They also assessed 4 lifestyle behaviors: no current smoking, BMI <30, physical activity at least once a week, and a healthy diet pattern (consisting of increased amounts of fruit, nuts, vegetables, whole grains, fish, dairy, as well as reduced amounts of refined grains, processed meats, red meats, sugar sweetened beverages, trans fats, and sodium)
  • A favorable lifestyle was defined as at least 3 of the 4 healthy lifestyle factors, with an intermediate lifestyle being 2 of these factors.

Results:

  • 1230 cardiac events were observed in the ARIC cohort over 18.8 years, 971 in the WGHS cohort over 20.5 years, and 2902 in the MDCS cohort over 19.4 years
  • A risk gradient was noted across quintiles of genetic risk, pretty consistently among the studies, with a hazards ratio of 1.91 comparing the top vs. bottom quintile of risk scores, reflecting a 91% higher attributable genetic risk, controlling for age, sex, self-reported education level, and analysis of ancestry when available
  • Levels of LDL cholesterol were only modestly increased across categories of genetic risk, and genetic risk scores were independent of other cardiometabolic risk factors as well as the 10- year predicted cardiovascular risk
  • A family history of coronary disease was an imperfect surrogate for genotype-defined risk [perhaps part of the issue: several older studies i have seen have found pretty dramatic discordance between elicited family history of heart disease and actual known heart disease events in the family members, up to 35-40%; the Framingham study found a 17% discordance.]
  • Each of the lifestyle factors were associated individually with decreased coronary risk: non-smoking with a 44% decreased risk, BMI <30 with a 34% decrease risk, regular physical exercise with a 12% decreased risk, and a healthy diet with a 9% decreased risk
  • People with unfavorable lifestyles (<2 of the 4) had higher rates of hypertension and diabetes, higher BMI, and less favorable lipids; overall they had an adjusted hazard ratio of cardiac disease of approximately 2 in each of the three prospective cohorts (i.e., twice the risk).
  • Within each genetic risk category, lifestyle factors were strong predictors of coronary events.
    • Adherence to a favorable lifestyle (at least 3 of the 4 factors) vs. an unfavorable lifestyle (<2) was associated with a 45% lower relative risk in the group at low genetic risk, a 47% lower relative risk among those when intermediate genetic risk and 46% among those at a higher genetic risk. [i.e., the relative risk was equivalently lower in each genetic subgroup with more favorable lifestyle]
    • Among people at high genetic risk, in the 3 prospective cohorts the 10-year coronary event rates were also approximately twice as high in those with unfavorable vs. favorable lifestyles.
  • Further analysis showed that those with high genetic risk but healthy lifestyles had about the same number of cardiac events as those with low genetic risk but unhealthy lifestyles in each of the 3 prospective cohorts, though this was partially explained by differences in traditional risk factors
  • There were limited data for the black population and generally less well-validated genetic loci for coronary disease, although evaluating the black cohort in the ARIC study yielded similar findings
  • In the BioImage study, both genetic and lifestyle factors were associated with higher CAC scores, and within each genetic group there was a significant trend toward decreased CAC scores in those with a healthier lifestyle

Commentary:

  • This study validates that both genetic risk as well as lifestyle are continuously related to cardiac events, and that the genetic risk is largely independent of traditional cardiac risk factors
  • But, this study really undercuts genetic determinism. In fact, there was the same relative decrease in cardiac risk in each of the genetic subgroups (high vs. low genetic risk) with improved lifestyle. And, in terms of absolute risk, those at the highest genetic risk had much more benefit from a healthy lifestyle change than those of lower genetic risk.
  • One general concern I have, tangentially related to the above, is with the availability of genetic analyses for the general population (e.g., 23andme, which advertises “discover what your 23 pairs of chromosomes say about you”, and costs only $199). My concerns are in part that we don’t really know how to interpret many of these genetic findings prospectively, but also that this analysis may reinforce a sense of genetic determinism in the population.
  • It was also a little surprising that the benefits for the individual lifestyle markers were what they were. We do know from prior studies that smoking cessation is the single most beneficial individual intervention in decreasing cardiac risk, as also suggested in this study which found that current non-smoking was associated with the lowest cardiac risk . What was most surprising to me was that the benefit of exercise and healthy diet were not so profound: I suspect that the quantification of diet and exercise was likely not that accurately represented as a bimodal, all-or-none issue (e.g., unclear what the cutpoint was for defining a healthy vs. unhealthy diet, and using one day of exercise a week without even quantifying the amount/type of exercise makes these lifestyle markers hard to interpret, especially as compared to smoking or BMI which have clear bimodal cut-points)

So, I think this study provides some important information in dealing with patients. I have certainly seen many patients who feel that they are destined to die from heart disease because of their family history. This study provides a tool to speak even more convincingly with patients, in that those at higher genetic risk actually achieve the most benefit by improved lifestyle.

Primary Care Corner with Geoffrey Modest MD: Colchicine May Lower Cardiac Risk in Patients with Gout

14 Oct, 16 | by EBM

By Dr. Geoffrey Modest

There have been several articles suggesting that allopurinol is associated with decreased cardiovascular events (for example, see http://blogs.bmj.com/ebm/2016/04/04/hyperuricemia-allopurinol-decreases-cardiac-events/ ). This might be attributed to the cardiotoxic effects of hyperuricemia itself, or perhaps through its association with the metabolic syndrome (see the above allopurinol blog for more details, as well as http://blogs.bmj.com/ebm/2015/11/03/primary-care-corner-with-geoffrey-modest-md-uric-acid-lowering-cardiovasc-benefit-and-an-evolutionary-perspective/ for an evolutionary perspective).  However a recent study found that colchicine in patients with gout also seems to be associated with fewer cardiovascular events (see Solomon DH. Ann Rheum Dis 2015; doi: 10.1136/annrheumdis-2015-207984).

Details:

  • All patients were identified with a diagnosis of gout in their electronic record in a large academic hospital (99% accurate diagnosis, on a sample of 100 records) and linked them with cardiovascular outcome data and medication claims from Medicare.
  • 501 colchicine users (defined as those with colchicine prescribed, but no previous colchicine prescriptions in the past 90 days) and 501 nonusers. Mean follow-up 16.5 months
  • Mean age 73, 36% female, 72% white/18% black/4% Hispanic, 13% known CV disease, 10% prior heart failure, 38% diabetes, 40% on aspirin, 38% never smokers, BMI 30, 42% chronic kidney disease.
  • Primary outcome: MI, stroke, or TIA.
  • However, there were some significant differences between colchicine users and nonusers, including: hypertension in 77% of colchicine users and 28% of nonusers, statin use 50% vs. 16%, uric acid levels 8.4 mg/DL vs. 7.1 (but of note, only 278 of the 1002 patients actually had uric acid levels documented), 42% vs. 16% were on allopurinol, 42% vs. 9% were on NSAIDs, and 42% vs. 12% were on oral steroids.

Results:

  • 28 primary CV events were observed among colchicine users and 82 among nonusers, incidence rates per 1000 person-years were: 35.6 for users and 81.8 for nonusers.
  • With full adjustment (age, gender, race, history of CV disease and risk factors, as well as medications including NSAIDs, allopurinol, chronic kidney disease), colchicine was associated with:
    • 49% lower risk of all primary CV outcomes, HR 0.51 (0.30 – 0.88)
    • 73% reduction in all-cause mortality, HR 0.27 (0.17 – 0.43)
  • The curves for all of these outcomes were tending to splay apart over time. Of note, however, those who were on colchicine for the longest did have more cardiovascular events, with the group doing best being those who used colchicine less than three months.
  • Though only a quarter of the patients had uric acid levels checked, there was a similar trend by uric acid levels as with the primary analysis.

Commentary:

  • The putative mechanism by which colchicine might decrease cardiovascular events is through its down regulation of inflammatory cytokines and neutrophil chemotaxis, decreasing inflammation. And it does have clinical benefit in several inflammatory conditions including recurrent pericarditis, familial Mediterranean fever, …
  • As with all observational studies, there may be inherent biases. They did try to control for underlying diseases, but there still could be some bias to not using colchicine in those who were sicker. There might also have been a bias that those on colchicine may have been more willing to take medications, which could elicit a higher placebo effect. It would be really helpful to have a controlled trial of chronic allopurinol vs. chronic colchicine use in patients with recurrent gout attacks, both to compare the efficacy in preventing gout as well as differences in cardiovascular outcomes.
  • So, how did this study affect our clinical practice? Probably not a lot, without a study showing clearly that colchicine is as effective as allopurinol/hypouricemic agents in decreasing cardiovascular events. Since there are still more data supporting the cardioprotection of hypouricemic agents, I will still continue with them primarily. However, in the remote past, I had many patients on chronic colchicine for recurrent gout with excellent effectiveness in gout attack prevention. At a dose of 0.6 mg per day (though some clinicians used 0.6 mg bid), colchicine was very well-tolerated and seemed to have fewer adverse effects than allopurinol. So, as a result of this current study, I am more inclined to use chronic colchicine again, especially if someone is intolerant of the hypouricemia (In this latter case, I had moved more to treating the recurrent gout attacks with intra-articular steroids.)

Primary Care Corner with Geoffrey Modest MD: Hepatitis C Treatment Leads to Lower Complication Rate in Prospective Study

11 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A large prospective cohort study confirmed that successful treatment of hepatitis C infection led to many benefits, including decreased hepatocellular carcinoma (HCC) and hepatic decompensation, but also lower cardiovascular risk, bacterial infections and both liver- and nonliver-related overall mortality (see doi:10.1053/j.gastro.2016.09.009, though at this point the paper was an accepted manuscript and not formally published).

Details:

  • 1323 patients from the prospective CirVir cohort from 335 centers in France recruited from 2006-2012 with biopsy-proven cirrhosis, Child Pugh class A, and no prior liver complications. All patients received anti-HCV with interferon, and then direct antiviral agents (DAAs) starting in February 2014, had ultrasound every six months and endoscopic evaluation. Analysis of data was done January 2016.
  • 63% male, mean age 55, AST 58, ALT 63, normal serum albumin/bilirubin/prothrombin time, 31% with esophageal varices, 68% genotype 1, 16% genotype 3, 5% HIV co-infected, 32% excessive alcohol consumption and 25% ongoing alcohol consumption, 38% current smokers, 31% past substance abuse, BMI 26, 90% diabetes, 9% past CV event
  • Follow-up average of 58.2 months.
  • 94% of the patients had undergone antiretroviral therapy at the time of inclusion, of whom 20% had SVR. During follow-up, 1183 treatments were recorded in 793 patients, 287 had first-generation anti-protease agents in genotype 1 infections and 328 had DAA regimens.
  • Propensity match scoring was used to control for morbidities, etc by multivariate analysis, to decrease confounding by indication of treatment or capacity to achieve sustained viral response (SVR)

Results:

  • Overall 215 patients (16%) had at least one episode of liver decompensation or GI bleeding; 422 patients (32%) developed a first hepatic focal lesion of which 55% were considered indeterminate or benign. A total of 1550 extrahepatic events occurred in 697 patients (140 vascular events, with 33 having heart failure, 30 ischemic heart disease), 204 patients had a bacterial infection (27% UTI, 25% pulmonary infections, 11% spontaneous bacterial peritonitis, 12% skin infections). 83 patients had extrahepatic cancers (lymphomas 15, gynecologic 15, colorectal 12, lung 12, oral 12)
  • Factors related to complications:
    • HCC: age, low platelet count, high GGT levels, past excessive alcohol consumption. In those with SVR, risk factors included low PT, low platelet count, high GGT, high AST, and some metabolic syndrome features (BMI >25 and or diabetes and/or dyslipidemia; overall found in 60% of the population).
    • Bacterial infection: age, low albumin, low GFR
    • Cardiovascular events: low albumin, smoking, past history of CV events, hypertension
    • Hepatic decompensation: age, low platelet count, high GGT levels, low albumin, esophageal varices.
    • Overall death: age, low platelet count, high GGT, low albumin, past excessive alcohol consumption, past history CV events, tobacco, hypertension. In those with SVR, only 18 patients died but these patients had low platelet count, diabetes, a past history of cardiovascular events, or a past history of malignancy
    • Extrahepatic cancer: age
  • 668 patients (50.5%) achieved an SVR, associated with (vs. those not achieving SVR):
    • 71% decrease in HCC, HR 0.29 (0.19 – 0.43), p<0.001
    • 74% decrease in hepatic decompensation, HR 0.26 (0.17 – 0.39), p<0.001
    • 58% decrease in cardiovascular events, HR 0.42 (0.25 – 0.69), p=0.001
    • 56% decrease in bacterial infections, HR 0.44 (0.29 – 0.68), p<0.001
    • 73% decrease in total mortality, HR 0.27 (0.18 – 0.42), p<0.001
    • There was no effects of SVR on extrahepatic cancers
  • Similar results to the above were obtained through propensity score-matched population.
  • The curves for HCC, hepatic decompensation, and bacterial infections continued to increase in those without SVR over 108 months of follow-up, but were basically flat in those with SVR. The curves for major adverse cardiac events continued relatively parallel after about five years, and overall survival diverged till about 84 months, then curves were parallel.
  • Overall, there was no difference in outcome in SVR patients whether they achieved their SVR through interferon-based regimens or DAAs, though the follow-up in the latter group was too short to be definitive.

Commentary:

  • This large study adds to prior studies finding that those who achieved SVR had improvement in liver-related complications: including fibrosis and necrosis, portal hypertension and splenomegaly, HCC, risk for liver-related mortality and transplantation; as well as some non-liver related ones: non-Hodgkin’s lymphoma and other lymphoproliferative disorders, and all-cause mortality (see http://www.hcvguidelines.org/full-report-view , which has a regularly updated review of hepatitis C overall, with emphasis on therapy). This new study basically confirms the liver-related benefits but also includes non-liver benefits in cardiovascular and infectious diseases.
  • One important feature of this study is that this one involved a more inclusive prospective cohort study of HCV-treated cirrhotic patients, with most of the prior studies being retrospective cohorts and observational. This was also a rigorous study which required biopsy-proven cirrhosis.
  • There were a few findings of potential concern: in those who developed SVR, the incidence of hepatic decompensation seemed to be lower in those who were on interferon-based regimens. Those who had a protease inhibitor-based regimen had a higher risk of bacterial infections. But overall, there were no clear differences based on the regimens to achieve SVR.
  • The increase in cardiovascular events could be related to several conditions, including adverse cardiac effects from the metabolic syndrome, and the chronic inflammation associated with ongoing hepatitis C infection. There even is argument for a direct effect of HCV itself on cardiovascular disease (e.g. there seems to be a correlation between higher HCV viral loads and cardiovascular morbidity)
  • Of note, there was a recent FDA alert about DAAs (see http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm523690.htm ), where they note that there were 24 cases of patients dually-infected with hepatitis B and C who had reactivation of their hepatitis B.
  • So, this current study brings up  several points regarding successful treatment of hepatitis C:
    • It reinforces the remarkable decrease in many adverse hepatic and extra-hepatic outcomes of hepatitis C infection in those with cirrhosis
    • It tangentially raises the likely utility of treating chronic hepatitis C infections earlier, in the pre-cirrhotic and even pre-fibrotic stages, since many patients with SVR still have complications (though much less than without SVR). Also, from other studies, those with fibrosis often do not get significant reversal of their fibrosis with SVR and are therefore still potentially at risk for HCC and subject to on-going HCC surveillance
    • Unfortunately, this study looked only at hard endpoints: other studies have found important improvements in quality of life, including physical, emotional and social health.

Primary Care Corner with Geoffrey Modest MD: CPAP Does Not Reduce Cardiovasc Risk

3 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent article looked at patients with moderate-to-severe obstructive sleep apnea (OSA) and documented cardiovascular disease (CVD), finding no reduced risk of adverse cardiovascular outcomes by using CPAP (see DOI: 10.1056/NEJMoa1606599).

Details:

  • 2717 patients aged 45-75 who had moderate-to-severe OSA as well as coronary or cerebrovascular disease were randomized to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group)
  • Mean age 61, 81% male, 64% Asian/25% white, 51% with coronary artery disease/49% cerebrovascular disease, 79% hypertensive, 44% stroke, 33% MI, 30% diabetic, 15% smokers, 78% on BP meds/57% statins/75% aspirin/27% diabetic meds, BMI 29, apnea-hypopnea index (AHI) 29 (moderate-to-severe obstructive sleep apnea), 84% snoring almost every day, but minimal daytime sleepiness
  • Primary composite end point was: death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack
  • Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.
  • Results:
    • In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night (in beginning 4.4, decreasing to 3.5 hours/night by 12 months), and the mean AHI decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up, reflecting good control. 42% adhered to treatment for >4 hrs/night.
    • After a mean follow-up of 3.7 years:
      • Primary end-point event occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) [HR 1.10; (0.91 to 1.32) P = 0.34]. No significant effect on any individual or other composite cardiovascular end point was observed, and the trend was actually for more events in the CPAP group.
      • CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood, with greater reductions in anxiety and depression (25-30% lower). no difference in road-traffic accidents or accidents caused by injury
    • No difference in subgroups: region (China vs other), age, sex, severity of OSA, BMI, daytime sleepiness, type of CVD, diabetes.
    • There were differences in patient characteristics in those who used CPAP > vs < 4 hours/night: more were Caucasian/European, men, had baseline CAD, hypertension, and fewer had TIA/stroke. Using propensity-score matching, there were 86 events in the CPAP group and 98 in usual-care: non-significant (i.e., no benefit even in the subgroup who used CPAP for > 4 hours/night)

Commentary:

  • The indications for CPAP seem to continue to decrease over time. There is pretty good documentation that OSA is associated with hypoxemia and sympathetic stimulation, elevated blood pressure especially in the AM, inflammation, oxidative stress, metabolic syndrome/insulin resistance/type 2 diabetes (which seems to independent of the obesity common in both conditions), 2-3x increased risk of NAFLD (also apparently independent of obesity/diabetes), hypercoagulation, right-sided heart failure. There are several observational studies suggesting that there is an association with cardiovascular events (esp stroke). And there are studies finding that using CPAP lowers the blood pressure, but only a little (2-3 mmHg, but can be up to 6-7 mmHg in those with resistant hypertension, though a recent RCT found a 3-4mmHg decrease); and improves insulin sensitivity and endothelial function. And observational studies show that it lowers cardiovascular events in those adherent to treatment. Another study found a 64% relative and 28.5% absolute risk reduction in those using CPAP in a nonrandomized but prospective 6 year study, concluding “OSA treatment should be considered for primary and secondary cardiovascular prevention, even in milder OSA” (see Buchner NJ. Am J CritCare Med 2007; 176 (12): 1274), advocating for more aggressive CPAP usage.
  • The concerns about CPAP are: that OSA is remarkably common, including 20-30% of males and 10-15% of females, though this depends on how OSA is defined and what the cutpoints are for the AHI (these percentages are if one uses an AHI>5/hour cutpoint); OSA seems to be much more common in those with underlying cardiovascular disease, cited at 40-60%; but CPAP is a pretty significant intervention (very difficult for many patients to use CPAP machines/uncomfortable, and in this study, the average was only 3.3 hours/night, which is similar to general clinical practice). Using CPAP therefore only makes sense if there is real clinical improvement.
  • A prior study was done in Spain (see Barbe F. JAMA 2012; 307(20): 2161) which randomized 357 patients to CPAP, 366 control. All patients had AHI of  >= 20/hr and no significant daytime symptoms; and they excluded anyone with prior cardiovascular event (i.e., much lower cardiovascular risk than those in the current study). In this 4-year study, as with the above study, there was no difference in cardiovascular events. Of note there was no difference in events when assessing those with the highest AHI levels or % of time with SaO2 <90%. Median CPAP usage was 5 hours, but those who used the CPAP >4 hours did have a 28% [HR 0-.72 (0.52-0.98), p=0.04)] lower incidence of hypertension or cardiovascular event. But looking specifically at cardiovascular events, there was a nonsignificant trend to lower CVD events (I should add here that 60% used the CPAP>4 hours, and this more adherent group may have done other healthy changes to decrease their risk of cardiovascular events. and these healthier things may have influenced the outcome more than the CPAP). Similarly if look at amount of time with SaO2<90%, the less time the fewer events.
  • So, overall, this current study showed very little cardiovascular benefit in many patients at high risk for CVD events and with pretty severe OSA. Although it is true that people used the CPAP only for 3-4 hours/night, this seems to be pretty much the range of usual CPAP usage, and they did find a dramatic decrease in AHI. My sense is that the indications for CPAP, a pretty significant and difficult intervention for many patients, have decreased considerably over time (early commentators suggesting that we should use it to prevent right-heart failure, or improve hypertension control, or decrease cardiovascular events/metabolic syndrome, etc.). Now, by far the major argument for CPAP for the vast majority of people, it seems to me, is for symptom control when patients are not sleeping well and having daytime somnolence or functional/psychological impairment(depression/anxiety, etc.) from inadequate sleep.

Primary Care Corner with Geoffrey Modest MD: W-3 Fatty Acids Decrease Heart Disease

15 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A meta-analysis including 19 studies and >45K individuals from 16 countries supported a small but significant cardiovascular benefit for both seafood and plant-derived w-3 fatty acids (see doi:10.1001/jamainternmed.2016.2925).

Details:

  • 19 studies from 16 countries (US, Australia, Costa Rica, UK, Italy, Finland, Sweden, Singapore, France, Ireland, Germany…) with  45,637 individuals and 7973 total CHD (coronary heart disease), 2781 fatal CHD and 7157 nonfatal MI events (the studies did not all break down the CHD events the same way, so these numbers do not add up)
  • Median baseline age 59, 63% male, BMI 26, up to 30% current smokers. Most were white, though some studies had racial/ethnic diversity. Overall alcohol consumption, mostly up to 1 drink/d. Fish oil supplements used infrequently. Median 10 year of follow-up
  • Assessed biomarkers for w3 polyunsaturated fatty acids (measured in whole plasma or tissue, which turned out to be better predictors than adipose tissue and cholesterol ester estimates):
    • Seafood-derived: eicosapentaenoic acid (EPA; 20:5w-3), docosapentaenoic acid (DPA; 22:5w-3), and docosahexaenoic acid (DHA; 22:6w-3)
    • Plant-derived: a-linolenic acid (ALA; 18:3w-3)
  • Results: significant associations were as follows, with multivariate-adjusted analyses, per 1-SD increase in the biomarkers:
    • ALA:
      • Fatal CHD: 9% decrease, RR 91 (95%CI, 0.84-0.98)
    • DPA:
      • Fatal CHD: 10% decrease, RR 90 (95%CI, 0.85-0.96)
      • Total CHD: 6% decrease, RR 0.94; 95%CI, 0.90-0.99),
    • DHA:
      • Fatal CHD: 10% decrease, RR 90 (95%CI, 0.84-0.96)
    • EPA:
      • Only reached borderline significant benefit

Commentary:

  • The prior studies on w-3 polyunsaturated fatty acids and CHD events are a bit mixed, with many methodologic problems (including relying on dietary recall), and few have looked at plant-derived w-3’s
  • Though there was no comment on what “fully-adjusted multivariate analysis” meant, likely because the studies varied, there was a comment that “No significant differences in associations of ω-3 PUFA biomarkers with incident CHD events were observed by age, sex, ω-6 PUFA (linoleic acid or arachidonic acid) concentrations, type 2 diabetes status, statin use, regular aspirin use, year of biomarker sampling, or (for ALA) EPA, DPA, and DHA concentrations”
  • In terms of biological plausibility, there are randomized controlled trials showing these w-3 fatty acids lower triglyceride levels, blood pressure, heart rate, and improve endothelial function, membrane stabilization through changes in lipid composition (which could decrease ischemia-mediated ventricular fibrillation, and possibly explain why the clinical improvement was more evident for fatal events) and myocardial oxygen demand, all of which could translate into improved clinical cardiac outcomes.
  • One highlight in the above study is the equal association of the plant-derived ALA to the seafood-derived rest of them: there are also data showing ALA decreases thrombosis, arrhythmias and inflammation, and improves endothelial function. And for much of the world, plant-derived w-3 is more affordable and accessible. By my review, the best single source of ALA is flaxseed, then also canola oil, and walnuts (esp. English). Other pretty high sources (actually, better than fish on a weight basis when comparing to the fish w -3’s) include soybeans, oats (germ), dried beechnuts and butternuts).
  • There were some interesting subgroup analyses, showing that Chinese and African-American individuals may benefit more from w-3. ?why ?genetic component. ?how the food was prepared (minimally cooked vs deep-fried, etc.). It was also interesting that taking statins or aspirin did not affect the overall outcomes much, since they accomplish at least some of the positive biological effects as the w-3’s.
  • I am always concerned about looking at single foods or food additives. In part because we eat a variety of foods, vitamins, etc., and there are likely interactions between the food components as well as optimal balances of different ones. And, even though this study was perhaps the best of the w-3 ones I’ve seen (in the sense that it combined lots of different studies from different areas, looked at hard-evidence both of actual w-3 levels in the body (vs dietary recall) as well as hard clinical endpoints, and seemed methodologically rigorous), there is always concern about the causal relationships in observational studies (i.e., did those who ate more w-3’s also do more other healthful behaviors (eat less red meat, eat more natural foods, do  more exercise, etc.)?
  • So, I do think this study adds to and deepens the literature that w -3’s are good for you (and, contrary to some prior articles/concerns, it seems that w -6’s did not counteract the benefits of the w-3’s).

 

Primary Care Corner with Geoffrey Modest MD: Air Pollution and Heart Disease

6 Jul, 16 | by EBM

By Dr. Geoffrey Modest

Yet another study found an increase in heart disease in people exposed to air pollution/fine-particulate matter exposure (see doi.org/10.1016/ S0140-6736(16)00378-0).

Details:

  • 6795 participants. Aged 45-84, enrolled in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) from 6 different US cities (Baltimore, Chicago, LA County, New York City, St Paul, Winston-Salem)
  • Median age 62, 53% women, 39% white, 12% Chinese, 27% black, 22% Hispanic), 50-80% with at least some post-high school education, 15% smokers, BMI 28, 45% with hypertension and SBP 128 mmHg, 12% diabetic, 15% on statins and cholesterol/HDL/LDL=190/50/115
  • Followed 10 years with repeated measurements of coronary artery calcium by CT (CAC score) as well as carotid artery intima-media thickness (CIMT); concentrations of fine particulate matter (PM5, which reflects particulate matter <2.5 mm in diameter) and nitrogen oxides (NOx) were estimated based on residence-specific spatio-temporal pollution concentration models, which include community-specific measurements, monitoring data and geographical predictors.
  • Baseline CAC was 145 Agatston units, which is already pretty elevated, but not so surprising for the demographics of the study (see https://www.mesa-nhlbi.org/Calcium/input.aspxfor the MESA CAC score: input age, sex, race/ethnicity and CAC score to get a sense of the meaning of the score)

Results:

  • Overall, CAC increased on average by 24 Agatston units/yrand CIMT 12mm/yr.
  • Participant-specific air pollutant concentrations averaged over the years 2000-2010 ranged: for PM5from 9.2-22.6 mg PM2.5/m3 and for NOx from 7.2-139.2 parts/billion (ppb) [PM2.5 highest in LA County, NOx highest in New York City]
  • For each 5 mg PM5/m3 increase, CAC progressed by 4.1 Agatston units/yr (CI 1.4-6.8), controlling for the usual suspects (age, sex, ethnicity, BMI, physical activity, smoking/second-hand smoke, employment, total and HDL cholesterol, triglycerides, statin use, neighborhood socioeconomic index, level of education, income)
  • For each 40 ppb increase in NOx, CAC progressed by 4.8 Agatston units/yr (0.9-8.7). This relationship was stronger in hypertensive, non-obese individuals and in those >65 yo.
    • No clear association with CIMT

Commentary:

  • There have been many studies over the past 1-2 decades finding a relationship between particulate exposure or air pollution with atherosclerotic disease (MI, strokes). The current study was a prospective long-term one which looked at the process of atherosclerosis itself. My reading of the literature is that CIMT is a much less accurate predictor of atherosclerotic events than the CAC (CIMT really measures arterial injury more than atherosclerosis itself). And CAC has really good sensitivity and specificity for clinical atherosclerotic events over an array of clinical settings (it’s the best of the nontraditional cardiac risk factors).
  • This study provides strong evidence that the relationship between particulate exposure/air pollution and heart disease is mediated through atherosclerosis (vs simply being from endothelial dysfunction, arrhythmias, ), that the process is dose-related and progressive, and that there would be a reasonable expectation that improving air quality would lead to improvements in atherosclerosis-related outcomes. Though I should add that there are also data from the MESA study that endothelial dysfunction may also play a role: see Krishnam RM. J Am Coll Cardiol 2012; 60:2158; and there was a small study at our health center in Boston finding an association between particulate exposure and cardiac autonomic function within hours of the exposure: see Lee M. Am J Cardiol 2016; 117:151)
  • Though I think this study is quite impressive regarding the relationship between air pollution and atherosclerosis, it would be interesting to see more granular data: was this as true for those with no underlying atherosclerosis by CAC at baseline? Also, was there a difference in actual clinical events (vs just changes in the surrogate marker of CAC; though as a perspective, there are a slew of other studies finding increased strokes/MIs)?
  • So, again, on an individual level, it is useful to incorporate air quality as one of our many risk factors for clinical atherosclerotic disease both in terms of nonpharmacologic therapies (weight, diet, exercise, stress reduction, etc.), perhaps with further education around minimizing exposure to air pollution on particularly bad days, and for use of meds (statins, ). And, on a society level, and especially with increasing pollution in many countries associated with “modernization” and perhaps exacerbated further by climate change, this study reinforces the importance of public health initiatives to decrease air pollution/particulate exposures.

http://blogs.bmj.com/ebm/2015/08/05/primary-care-corner-with-geoffrey-modest-md-comparison-of-the-2013-accaha-lipid-guidelines-to-atpiii/

http://blogs.bmj.com/ebm/2016/04/13/primary-care-corner-with-geoffrey-modest-md-coronary-artery-calcium-scores-from-regular-chest-cts/

Primary Care Corner with Geoffrey Modest MD: Migraine and Heart Disease in Women

1 Jul, 16 | by EBM

By Dr. Geoffrey Modest

Analysis of the Nurses’ Health Study found a significant increase in cardiovascular disease in those with migraine

(see http://dx.doi.org/10.1136/bmj.i2610 ).

Details:

  • 115 541 women aged 25-42 years at baseline and free of angina and cardiovascular disease were followed from the prospective Nurses’ Health Study II (from 1989-2011)
  • Mean age 35; BMI <25 in 68%, 25-30 in 19%; history hypertension 6%, hypercholesterolemia 12%, smoking 14%; no alcohol in 38%, up to 15 g/d in 58%; oral contraceptives in 12%.
  • 17 531 (15.2%) women reported a physician’s diagnosis of migraine (though no data on presence of aura, migraine frequency, or migraine meds)
  • Women with migraine were more likely to have hypertension, hypercholesterolemia, family history of MI, BMI>30 or be current smoker

Results:

  • 1329 major cardiovascular disease events occurred, and 223 women died from cardiovascular disease
  • Adjusting for potential confounding factors (age, cholesterol, diabetes, hypertension, BMI, smoking, alcohol, physical activity, postmenopausal estrogens, menopausal status, oral contraceptives, aspirin/acetaminophen/NSAID use, and family history MI), migraine was associated with an increased risk for:
    • Major cardiovascular disease (hazard ratio1.50, 95% confidence interval 1.33 to 1.69)
    • Myocardial infarction (HR 1.39, 1.18 to 1.64)
    • Stroke (HR 1.62, 1.37 to 1.92)
    • Angina/coronary revascularization procedures (HR 1.73, 1.29 to 2.32)
    • Cardiovascular disease mortality (HR 1.37, 1.02 to 1.83)
    • Associations were similar across subgroups of women, including by age (<50/≥50), smoking status (current/past/never), hypertension (yes/no), postmenopausal hormone therapy (current/not current), and oral contraceptive use (current/not current)

Commentary:

  • Several studies have found that migraine (specifically migraine with aura) is associated with increased risk of stroke
  • The Women’s Health Initiative found similar increase in cardiovascular disease (about the same +/- 50% increase as above), but only in those reporting migraine with aura
  • Several other studies from different countries (Taiwan, Iceland, as well as the American Migraine Prevalence and Prevention Study) have found similar results
  • How to explain the association?? Unclear. ?increased thrombogenic susceptibility, shared genetic markers, endothelial dysfunction, or inflammation (all have been shown in both migraine and cardiovascular disease). And a recent small study found that the combination of a statin and vitamin D, perhaps through their anti-inflammatory or endothelial effects, decreased the frequency of migraines (for analysis of this study, see prior blog: http://blogs.bmj.com/ebm/2016/01/06/primary-care-corner-with-geoffrey-modest-md-migraine-prophylaxis-with-simvastatinvitamin-d
  • So, it probably makes sense to include migraine (perhaps more so if aura present) in the overall gestalt of cardiovascular risk factors – e., it would be an added reason to strongly encourage lifestyle changes (smoking, appropriate weight, increasing fruits/veges in diet, exercise) in general, and it might sway me to use statins in those otherwise on the borderline for medical therapy

 

EBM blog homepage

Evidence-Based Medicine blog

Analysis and discussion of developments in Evidence-Based Medicine Visit site



Creative Comms logo

Latest from Evidence-Based Medicine

Latest from EBM