Tag Archives: Cardiovascular

How Much Fruit and Veg is Enough?

We are often told that we should be eating five (or is it now ten?) portions of fruit and vegetables each day to protect against, amongst other things, cardiovascular disease (CVD).[1] However, such recommendations are generally based on research conducted in people from Europe, the USA, Japan and China. There is little data from countries in the Middle East, South America, Africa or South Asia.

The PURE study (Prospective Urban Rural Epidemiology) set out to rectify this, recruiting 135,000 participants from 18 countries, ranging from high-income countries, such as Sweden, to low-income countries, such as India.[2] The research team documented the diet of these individuals at baseline (using questionnaires specific to each country), then followed them up for a median of 7.4 years, looking at cardiovascular-related clinical outcomes. As expected higher intakes of fruit, vegetables and legumes were associated with lower incidences of major CVD, myocardial infarction, and mortality (cardiovascular-related and all-cause). However, the hazard ratio for all-cause mortality was lowest for three to four servings (375-400g) per day (0.78, 95%CI 0.69-0.88), with no significant decrease with higher consumption.

It is more likely that consuming around 375g of fruit/vegetables/legumes per day will be within the financial reach of people living in poorer countries, compared to the various recommendations of 400-800g that are often seen in Europe and North America. Before we ditch that extra snack of carrot sticks, however, it is important to note that factors such as food type, nutritional quality, cultivation and preparation are likely to vary between countries, while other clinical outcomes, such as cancer, were not looked at in this study.

The authors are continuing to enrol more participants, and are hoping to re-examine their results in the future.

— Peter Chilton, Research Fellow

References:

  1. Oyebode O, Gordon-Dseagu V, Walker A, Mindell JS. Fruit and vegetable consumption and all-cause, cancer and CVD mortality: analysis of Health Survey for England data. J Epidemiol Community Health. 2014; 68(9): 856-62.
  2. Miller V, Mente A, Dehghen M, et al. Fruit, vegetable, and legume intake, and cardiovascular disease and deaths in 18 countries (PURE): a prospective cohort study. Lancet. 2017.
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A Device for Failing Hearts

Back in 2005 I was approached by Sally Davies, then languishing as deputy director general of Research and Development, and asked to evaluate the utility of a trial of left ventricular assist devices (LVADs) for heart failure. We elicited a Bayesian prior from a chapter of surgeons from the American Society of Heart Surgeons. This prior was the basis for a value of information study,[1] which suggested that expensive LVAD technology might be a bridge too far for the hard-pressed NHS. Anyway, the world moves on and the New England Journal of Medicine has recently carried out a trial comparing two different LVADs, one more sophisticated (type 3) than the original version we studied (type 2).[2] The latest version had less problems with clotting up of the device, but survival free of a serious stroke at six months was similar, at over 80% in both groups – quite high considering how sick these patients were. The article has some extremely good diagrams explaining the devices. These devices are sometimes used to rest the heart, for example in a case of inflammation of the heart muscle. Most often they are used when the heart muscle packs up permanently, say as a result of heart attacks. In that case LVADs can be used to keep a person alive until a match can be found for a heart transplant, so called ‘bridge to transplant’, or as a permanent solution. However, I think the devices are themselves a bridge to a more subtle regenerative medicine approach based on stem cells.

— Richard Lilford, CLAHRC WM Director

References:

  1. Girling AJ, Freeman G, Gordon JP, Poole-Wilson P, Scott DA, Lilford RJ. Modeling payback from research into the efficacy of left-ventricular assist devices as destination therapy. Int J Technol Assess Health Care. 2007; 23(2): 269-77.
  2. Mehrea MR, Naka Y, Uriel N, et al. A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure. New Engl J Med. 2017; 376: 440-50.

Recent History of Anti-Hypertensive Treatment Trials

An interesting essay by Pfeffer and McMurrary traces the recent history of trials of anti-hypertensive therapy.[1] The authors chronicle the scientific evidence that has accumulated to show that treating hypertension lowers the risk of stroke, heart disease and death; that systolic blood pressure is very important; that outcomes are improved, even if the starting blood pressure is only slightly raised (particularly in diabetes); but that it is also possible to try too hard to control blood pressure. No mention here of salt, which is important in the genesis and maintenance of hypertension. However, this is a readable account of how the scientific and ‘social’ discovery of how to treat the ‘silent killer’ that is hypertension progressed hand in hand.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Pfeffer MA, & McMurrary JJV. Lessons in Uncertainty and Humility – Clinical Trials Involving Hypertension. New Engl J Med. 2016; 375: 1756-66.

How Much Exercise Do You Need?

We know exercise reduces the incidence of cancer, diabetes and cardiovascular disease, but how much is needed? The WHO answer to this question is at least 600 on a standardised measure of total (work-related plus leisure) exercise called Metabolic Equivalent Tasks, or METs. This is the ratio of energy expenditure while performing an activity to expenditure at rest. Running for 75 minutes per week, atop of an otherwise sedentary life, yields the WHO standard of 600 METs. Better than nothing, but not enough according to a massive and sophisticated meta-analysis [1] – 2,000 to 4,000 METs are necessary to achieve material benefit (250 – 500 minutes of running). After this threshold, further gains with yet more exercise are nugatory. So lots of exercise is ideal, but excessive exercise is a fetish that wastes time. I aim to do two hours of ‘spinning’ and 90 minutes of doubles tennis each week. Let’s say spinning has an MET of 10, then I spend 1200 MET minutes spinning. If doubles tennis consumes 3 METs, then I spend 270 MET minutes. So my total METs is 1470 – not quite optimal. This study does not shed light on whether 2,000 METs spent in short bursts is better or worse than the same energy expenditure doing something really tedious, like lengths in a swimming pool. For that we need a study comparing “weekend warriors” with people who take similar amounts of exercise, but spread more evenly over the week.[2] The study was based on answers to questionnaires sent to participants in two huge cohort studies – the Health Survey for England and the Scottish Health Survey. The study replicates a link between exercise and overall mortality, cardiovascular mortality, and cancer mortality. However, the pattern of exercise does not seem to make much difference to the risk reduction.

— Richard Lilford, CLAHRC WM Director

References:

  1. Kyu HH, Bachman VG, Alexander LT, et al. Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013. BMJ. 2016; 354: i3857.
  2. O’Donovan G, Lee I-M, Hamer M, et al. Association of “Weekend Warrior” and Other Leisure Time Physical Activity Patterns With Risks for All-Cause, Cardiovascular Disease, and Cancer Mortality. JAMA Intern Med. 2017.

More on Fats and Their Effect on Cholesterol, Heart Disease, and Death

The accumulating evidence on the lack of association between eating saturated fat and heart disease has featured in previous posts.[1] [2] An intriguing re-analysis of an RCT carried out in nursing homes and hospitals for mental illness has recently been published in the BMJ.[3] In this trial saturated fats were replaced in the diet by polyunsaturated fats. The now familiar story was confirmed; yes, the polyunsaturated fat is associated with lower cholesterol levels, but no, there was no hint of a decrease in heart attack or all-cause mortality in the low fat group. The authors then carried out a systematic review, finding five RCTs examining the same hypothesis. They provided strikingly similar results; the meta-analysis corroborated the nursing home study. One intriguing point made in an accompanying editorial [4] is that the climate was so heavily slanted towards the fat and cholesterol hypothesis that the trial, which ended in 1973, was not published until 1989. But opinion has eventually caught up with the evidence and US dietary guidelines have finally removed dietary cholesterol and fat from the list of foods that should be avoided.[5] But note this point – the fact that saturated fats are no worse than polyunsaturated fats does not mean that there are not yet better sources of calories. And, yes, plants are better than meat, butter, etc. They are boring to eat, of course, but they are probably the best source for most of our calories.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford R. More on Diet. NIHR CLAHRC WM News Blog. 14 August 2015.
  2. Lilford R. On Diet Again. NIHR CLAHRC WM News Blog. 23 October 2015.
  3. Ramsden CE, Zamora D, Majchrzak-Hong S, et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ. 2016; 353: i246.
  4. Veerman JL. Dietary fats: a new look at old data challenges established wisdom. 2016; 352: i1512.
  5. US Department of Health and Humans Services and US Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 8th Washington, D.C.: USDA, 2015

 

 

Trial of Two Methods of Out-of-Hospital Resuscitation for Cardiac Arrest with an Interesting Design

Cluster trials very seldom use a cross-over design for the reason that it is typically tricky to withdraw a cluster level intervention once it has been introduced. However, as in clinical trials, the cross-over design is very powerful statistically (yields precise estimates) in those situations where it is feasible. Such was the case in a cluster trial of methods for cardio-pulmonary resuscitation.[1] One hundred and fourteen clusters (emergency medical services) participated. Adults with non-trauma related cardiac arrest were managed (according to cluster and phase) with either:

  1. Continuous chest compressions with asynchronous ventilations ten times per minute (experimental method); or
  2. Compressions interrupted to provide ventilation at a ratio of 30 compressions to two ventilations (standard method).

Nearly 24,000 people with cardiac arrest were included in the study and the survival rate with continuous compressions was slightly lower (at 9.0%) than with the standard interrupted method (at 9.7%). The result was not quite significant on standard statistical analysis. The CLAHRC WM Director thought the interrupted method would seem to be the one to go for, but the accompanying editorial was equivocal [2] – it would appear that even a trial of 24,000 participants, albeit in clusters, was not enough to resolve the issue. However, the trial methodology is certainly interesting.

— Richard Lilford, CLAHRC WM Director

References:

  1. Nichol G, Leroux B, Wang H, et al. Trial of Continuous or Interrupted Chest Compressions during CPR. New Engl J Med. 2015; 373(25): 2203-14.
  2. Koster RW. Continuous or Interrupted Chest Compressions for Cardiac Arrest. New Engl J Med. 2015; 373(25): 2278-9.

Multi-Morbidity

Guidelines are built in a solipsistic way around individual diseases and do not take into account the fact that most patients have more than one disease? Well this is not quite true; statins trials have been tested over a range and mix of conditions. Nevertheless, most trials are based on a rather ‘clean’ population. This creates three theoretical problems:

  1. Drugs prescribed for one disease may interact with those prescribed for another. For example, non-steroidals agents administered for osteoarthritis may interact with warfarin given for atrial fibrillation.
  2. Drugs prescribed for one disease may interact directly with another disease. Beta-blockers prescribed for hypertension may aggravate asthma, for example.
  3. Drugs may be less effective in treating the target disease when lots of diseases are present.

The first problem is well known – polypharmacy, apart from being bothersome, can be dangerous, as in the example cited. However, e-prescribing can reduce this risk, not just theoretically, but empirically.[1]

The second problem is also well documented, and it too can be tackled by e-prescribing, given a sufficiently data-rich IT set.[2]

The third problem, that multi-morbidity may affect the effectiveness of treatment for the index condition, has received less attention. There are theoretical reasons why multi-morbidity may attenuate effectiveness – for example, by reducing adherence to treatment. There are also theoretical arguments for an augmented effect when diseases share a common pathway targeted by the drug – inflammatory mechanisms for instance. This issue has now been investigated empirically in a recent paper [3] and editorial [4] in the BMJ. Tinetti and colleagues studied nine drugs shown in RCTs to decrease risk of death in people with cardiovascular disease. They used a database of 8,578 Americans who all had at least one condition in addition to the index cardiovascular disease. The hypothesis that effectiveness is affected by the presence of multi-morbidity was testable because many (nearly half) of the patients in the database had not received the drug that had been shown to be effective for their condition in RCTs. So the outcomes of those where the drug was indicated and prescribed could be compared to those where it was indicated but not prescribed. The results anticipated from the RCTs were replicated among the database patients – in other words, multi-morbidity did not modify treatment effectiveness in terms of adjusted hazard ratios.

Of course, such an observational study is beset with selection biases, including ‘healthy user bias’, whereby those who take medicines have a better prognosis a priori, and ‘immortal time bias,’ whereby some of those who would have received the intervention in an RCT are just not there to be counted in the database because they have died. In other words, receiving or not receiving the indicated drug may not be a good instrumental variable. Nevertheless, the results were adjusted for as many confounders as possible and this provides a measure of assurance that drugs produce anticipated effects, notwithstanding multi-morbidity. CLAHRC WM has an active theme of work in tailoring care according to patient preference, and this study is certainly highly relevant to this project. The CLAHRC WM Director makes the further point that if the relative risk reduction is the same in patients with multi-morbidity and those with single diseases, and if the multi-morbidity is associated with higher baseline morbidity/mortality, then the absolute risk reduction will be higher in multi-morbid than in uni-morbid patients

— Richard Lilford, CLAHRC WM Director

References:

  1. Nuckols TK, Smith-Spangler C, Morton SC, et al. The effectiveness of computerized order entry at reducing preventable adverse drug events and medication errors in hospital settings: a systematic review and meta-analysis. Syst Rev. 2014; 3: 56.
  2. Avery AJ, Rodgers S, Cantrill JA, et al. A pharmacist-led information technology intervention for medication errors (PINCER): a multicentre, cluster randomised, controlled trial and cost-effectiveness analysis. Lancet. 2012; 379: 1310-9.
  3. Tinetti ME, McAvay G, Trentalange M, Cohen AB, Allore HG. Association between guideline recommended drugs and death in older adults with multiple chronic conditions: population based cohort study. BMJ. 2015; 351: h4984.
  4. Muth C & Glasziou PP. Guideline recommended treatments in patients with multimorbidity. BMJ. 2015; 351: h5145.

Very Different Results from RCT and Observational Studies?

The CLAHRC WM Director lives only a few doors down from the Edgbaston golf course. The club house is a fine Georgian building and was the home of William Withering – a member of the Lunar Society and the person who discovered the cardiac-stimulating drug digitalis (digoxin). Foxglove plants, the natural source of digitalis, still grow in profusion. The CLAHRC WM Director prescribed this medicine frequently when working as a junior doctor on the medical wards. However, the drug fell from grace when many observational studies showed that use of the medicine was associated with an increased risk of death in patients with heart failure. However, a recent meta-regression [1] from Birmingham, London and Melbourne showed that the more care that was taken to reduce the risk of bias, the smaller the estimated increase in mortality, ending up with RCTs showing a neutral effect. The source of bias is obvious – doctors prescribe the medicine for their sickest patients, and the observable prognostic factors pick up only a proportion of the increased risk. The residual prognostic factors are subtle clues that experienced doctors can sense in a tacit way.

The accompanying editorial [2] uses these data to rubbish observational evidence, rather spectacularly missing a more subtle point – the greater the care taken in observational evidence, the more the risk of bias can be mitigated. Further mitigation is possible by adjusting for bias, using the method of Turner et al.,[3] thereby reducing point estimates and widening confidence limits into credible limits. We are considering using digoxin as an examplar of the method.

As for William Withering’s medicine; well it appears not to increase death rates after all, while both the observational and RCT evidence suggests that it reduces the need for admission. Two hundred and thirty years after his discovery, the scientific principles of the Englightenment that Withering espoused continue to refine our understanding of the medical uses of digoxin.

— Richard Lilford, CLAHRC WM Director

References:

  1. Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ. 2015; 351: h4451.
  2. Cole GD & Francis DP. Trials are best, ignore the rest: safety and efficacy of digoxin. BMJ. 2015; 351: h4662.
  3. Turner RM, Spiegelhalter DJ, Smith GC, Thompson SG. Bias modelling in evidence synthesis. J R Stat Soc Ser A Stat Soc. 2009;172(1):21-47.

More on Diet

For a very nicely written account of the evidence and reasoning behind recent changes in European and North American guidelines on fat intake, take a look at a recent BMJ editorial by Kromhout.[1] Advice to reduce total fat has been rescinded on both sides of the Atlantic. Increasing unsaturated fat consumption remains good news, eat lots of vegetables and don’t worry about the cholesterol content of the food itself. How about hot spicy foods loved by the CLAHRC WM Director? The very next editorial refers.[2] Good news! All-cause mortality was associated with a 14% (10-18%) reduction in all-cause mortality with specific reductions in both cancer and cardiovascular diseases. Cause and effect? Well the active compound of chilli, capsaicin, has many potentially beneficial biochemical effects – anti-oxidant, anti-microbial, anti-inflammatory, pro-biotic, and so on. But we have been here before – plausible biological explanations, followed by association studies, only to be disproven later – witness the fat story. So is it good that the CLAHRC WM Director is the kind of person who eats spicy foods, or are the spicy foods good?

— Richard Lilford, CLAHRC WM Director

References:

  1. Kromhout D. Where the latest US dietary guidelines are heading. BMJ. 2015; 351: h4034.
  2. Forouhi NG. Consumption of hot spicy foods and mortality. BMJ. 2015; 351: h4141.

More, Yes More, on ‘Pure, White and Deadly’

Over 11,000 people in the US National Nutrition Survey provide a sturdy cohort.[1] After adjusting for age, sex, and ethnicity, the risk of dying from cardiovascular disease climbs progressively and steeply with the proportion of calories that come in the form of added sugar. How much of this is due to sugar per se or total carbohydrates is less certain.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Dhurandhar NV, Thomas D. The Link Between Dietary Sugar Intake and Cardiovascular Disease Mortality. JAMA. 2015; 313(9):959-60.