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Cardiol- arrhythmia

Primary Care Corner with Geoffrey Modest MD: Sudden Cardiac Death in Young Athletes in the U.S.

2 Dec, 16 | by EBM

By Dr. Geoffrey Modest

A recent article looked at the demographics and epidemiology of sudden death in young athletes from the United States National Registry from 1982-2011 (see Maron BJ. Am J Med (2016) 129, 1170).

Details:

  • 2406 athlete deaths were reported to the registry, of whom 842 had confirmed cardiovascular causes associated with exercise, and with autopsy examination.

Results:

  • Mean age 18, 89% male, 46% white/43% African-American or other minority. 25% of deaths were during competition, 39% during practice, 17% during recreational activity, 18% unassociated with physical activity. 66% were junior high or high school, 19% in college. 35% playing basketball, 30% football.
  • Mortality rate in males exceeded females by 6.5-fold (1:121,691 and 1:787,392 athlete-years, respectively; p <0.001)
  • Cause of sudden death:
    • Hypertrophic cardiomyopathy (HCM): 302 athletes (292 males, 10 females), 36% of cases. 152 in African-American/138 in white
    • Congenital coronary anomalies: 158 athletes (127 males, 31 females), 19% of cases. 77 in African-American/72 in white
    • Indeterminate cause with left ventricular hypertrophy/possible HCM (autopsy finding abnormal hearts with increased heart weight and mild left ventricular thickening): 77 athletes (73 males, 4 females), 9% of cases. 31 in African-American/40 in white
    • Myocarditis: 57 athletes (46 male, 11 female), 7% of cases. 24 in African-American/30 and white
    • Arrhythmogenic right ventricular cardiomyopathy: 43 cases (31 male, 12 female). 8 in African-American and 35 in white

Commentary:

  • The US National Registry of Sudden Death in Athletes prospectively assembles data on the deaths of young athletes in competitive athletics, for those engaged in organized team or individual sports requiring regular training and competition, and have had sudden death. [not sure how inclusive this registry is for those just doing recreational sports — those in noncompetitive athletics may be significantly underreported]
  • This study confirms that hypertrophic cardiomyopathy was by far the single most common cause of sudden death in athletes in the US and was far more common in males and females. Coronary artery anomalies, arrhythmogenic right ventricular cardiomyopathy, and prolonged QT syndrome (though the latter only occurred in 18 individuals, 2.1% overall) were more frequent percentagewise in females.
  • Overall hypertrophic cardiomyopathy was more common in African-Americans than in whites and least common in white females.
  • The significant increase in cardiac deaths in males over females (greater than 6-fold) was also found in the French national registry (30-fold difference, though for marathon running it was 6-fold).
  • Structurally normal hearts were found in less than 5% of the athletes.
  • For a review of the American Heart Association and the American College of cardiology guidelines, see http://blogs.bmj.com/ebm/2015/01/21/primary-care-corner-with-geoffrey-modest-md-ekg-screening-in-young-peopleathletes/ .
  • Given the relatively high percentage of athletes dying from hypertrophic cardiomyopathy (and especially if you include those with LVH but considered to be indeterminate in terms of the specific HCM criteria), these data reinforce the American Heart Association recommendations for pre-participation screening (see or Maron BJ. JACC. 2014; 64: 1479). A brief review of the criteria:
    • The 14-element recommended screen for preparticipation in competitive athletes includes 7 items on personal history (chest discomfort on exertion, unexplained syncope or near syncope, excessive dyspnea or palpitations on exertion, heart murmur, elevated blood pressure, prior restriction from participating in sports, and prior testing of the heart by a physician), 3 on family history (sudden death before age 50 in at least one relative, disability from heart disease in a close relative prior to the age of 50, known history of specific cardiac diseases including hypertrophic cardiomyopathy, long QT syndrome, ion channelopathies, Marfan syndrome, clinically significant arrhythmias), and 4 items on physical exam including heart murmur likely to be organic, femoral pulses to exclude aortic coarctation, physical stigmata of Marfan’s, hypertension)
    • However, it is noted that personal/family history is often insensitive in identifying cardiac abnormalities, physical exam is often unremarkable (with some abnormalities only detectable by EKG, such as WPW or channel ionopathies), and even HCM is only detected by a murmur at rest in 25%, with an additional 50% on by Valsalva or cardiac exam while standing.
    • The EKG is sensitive but not so specific, given the number of false positives in young athletes
      • 5% of elite athletes have EKGs indistinguishable from HCM
      • The EKG is abnormal in more than 90% of people with HCM but the EKG changes are typically nonspecific (the specificity is about 50 to 60%, as per doi.org/10.1161/01.CIR.96.1.214)
      • The sensitivity and specificity for HCM is also largely determined by the cutpoints of voltages used in defining HCM. As noted, false-negative results occur in more than 10% of patients with documented HCM as well as more than 90% with congenital coronary anomalies. (Though 40% of sudden deaths in athletes in the Minnesota study were from diseases that could reliably be picked up by EKG)
      • The guidelines are more circumspect about using screening EKGs. Prior guidelines I’ve seen have been more strongly against using EKG. This one suggests that there are real concerns about the availability of trained people to read EKGs in younger people, there are lots of false positives leading to lots of echocardiograms (and potentially scaring/medicalizing the kids and families), and the cost to the system is quite high, given the large number of EKGs that would be done. And the issue in the US is different, for example, from the Italian data showing potential benefit from EKG screening, since that area of Italy (Veneto) had a very large % of sudden death from arrhythmogenic right ventricular cardiomyopathy which can be found on EKG more easily
    • The recommendations: use the 14 point screening guideline as above. Screening with 12 lead EKG’s may be considered in young healthy people age 12 to 25, not necessarily limited to athletes, mandatory and universal mass screening with EKG is not recommended for anyone.

So, sudden cardiac death, not surprisingly, is a pretty devastating though infrequent outcome for young and basically healthy kids.  My concerns are that sudden death clearly happens to those who are not super-competitive athletes (66% happened in junior high or high school; overall only 25% during competition and 39% during practice – and I’m not sure how complete the above database is, especially in those not in competitive athletics), and that these deaths are potentially preventable, to the extent that the questionnaire is reliable. I would not be surprised, for example, if the mortality in a kid with HCM were as great in an unfit 7th grader working hard on the basketball court for 15 minutes vs the remarkably fit varsity player…. It seems to me, given this, that we really should be screening all young kids with the questionnaire, perhaps on entry to junior high school, which really means also interviewing parents/guardians since kids are likely quite unreliable in knowing the specifics of the family history.

Primary Care Corner with Geoffrey Modest MD: Optimal blood pressure in patients with atrial fibrillation

30 Nov, 16 | by EBM

By Dr. Geoffrey Modest

It is unclear from the literature what the goal blood pressure should be in patients with atrial fibrillation, and this is not addressed by any of the guidelines. A post hoc analysis of the AFFIRM trial (Atrial Fibrillation Follow-up Investigation of Rhythm Management, a prospective trial assessing the strategy of rate versus rhythm control) looked retroactively at the relationship of achieved blood pressure and outcomes (see Badheka AO. Am J Cardiol 2014; 114: 727)).

Details:

  • 3947 patients in the trial were followed 6 years, noting their systolic and diastolic blood pressures (recorded after sitting quietly for at least five minutes) at baseline and at follow-up, divided into 10-mm Hg increments. The follow-up blood pressure was defined as the average of all available blood pressure measurements during each post-baseline visit
  • Mean age 69, and the following were significantly (and much) more frequent in patients who had lower blood pressure, with average percentages overall as follows:  60% in men, 70% hypertension, 40% coronary artery disease, 25% in patients with heart failure, 14% smoking
  • The endpoints assessed were all-cause mortality; the combination of all-cause mortality, ventricular tachycardia or fibrillation, pulseless electrical activity, significant bradycardia, stroke, major bleeding, MI, and PE as a composite secondary outcome.

Results:

  • All-cause mortality was observed in 614 people (15.6% of the group)
  • The incidence of all-cause mortality was lowest in those with BP 140/78 mm Hg, with a U-shaped curve. All-cause mortality was:
    • 9 fold higher in the group with systolic blood pressure <110; 1.9 fold higher in those with systolic greater >160
    • 3.9 fold higher in the group with diastolic <60; 1.8 fold higher in the group with diastolic >90
  • There was a similar U-shaped relationship to the composite secondary outcome.
  • Subgroup analyses also found a similar U-shaped curve with an increased all-cause mortality with blood pressure <110/60, including the following subgroups: whether or not they had CAD, hypertension, heart failure, or reduced ejection fraction.

Commentary:

  • One of the complicating factors in assessing the optimal blood pressure in patients with atrial fibrillation is that several of the drugs we use to control rate (e.g. beta-blockers and non-dihydropyiridine calcium channel blockers) also decrease blood pressure. So, one of the complicating factors in interpreting the association between lower blood pressure and increased mortality is inherent in this retrospective observational study: are those who require more medications to control their heart rate at a higher risk of death, just because their harder-to-manage atrial fibrillation is associated with higher mortality? And their higher incidence of hypotension merely reflects their need for more meds (which also lower their blood pressure) to control that rate???
  • Another large issue is the dramatic baseline comorbidities in those with lower blood pressure, reinforcing the fact that these were much sicker patients and raising questions as to whether the study could mathematically adjust for these covariates in their final analysis. The authors did control for age, history of hypertension, history of heart failure, history of MI or revascularization, history of stroke, diabetes, smoking status, use of warfarin, lipid-lowering therapy, diuretics, and which group they were randomized to in the AFFIRM  trial. However, given how apparently sick these patients with low blood pressure were, one wonders if there were other important variables not included (e.g. other medical conditions such as renal failure, or COPD –esp since those with lower BP also had lower BMI, or psychosocial conditions associated with higher mortality such as depression)???
  • And what really is the actual blood pressure in patients with atrial fibrillation? The automated blood pressure cuffs typically use an oscillometric methodology. Studies have shown that many of these cuffs are inaccurate in patients with atrial fibrillation (see DOI: 10.1111/jch.12545). And, a larger issue to me is that there is a large blood pressure variability between measurements in patients with atrial fibrillation, with one measurement picking up a particularly strong, forceful beat, leading to a systolic blood pressure that may be 30 to 40 mm Hg higher than other readings. Some people suggest averaging several recordings (??how many), but I have no idea whether this correlates with clinical events are not, what the best methodology for determining that clinically-relevant BP really should be, or what would be the optimal goal BP (which also requires a good clinical prospective study using a validated methodology. perhaps 24-hour ambulatory blood pressure monitoring with an approved and accurate automated cuff???). As mentioned, i have seen no guidelines address the blood pressure issue: either its measurement or management goals.
  • One issue that is found frequently in observational studies on hypertension is a J-shaped or U-shaped curve. Of note this tends not to be found in controlled trials (e.g. the SPRINT trial), suggesting that there may be a bias in the uncontrolled trials: those with lower blood pressure have higher mortality related to the fact that they have underlying diseases leading to both a lower blood pressure and higher mortality
  • Of note, there are some data suggesting that we do not need to be overly aggressive in controlling rate (see Van Gelder IC. N Engl J Med 2010; 362: 1363), which also raises the interesting question of whether those with aggressive rate control may have had increased mortality because their blood pressure was lower, balancing perhaps a clinical benefit of the lower rate (i.e. there might be some benefit for tighter rate control, but only in those who could achieve this without lowering their blood pressure too much). Unfortunately in this Van Gelder article they did not mention the achieved blood pressures in the 2 groups.
  • This AFFIRM article suggests that the target blood pressure in those with atrial fibrillation may be higher than in the general population. However, the methodologic issues above, to me, simply amplify the issue that there really are no good clinical data guiding us on either how to measure blood pressure or what the goal should be in those with atrial fibrillation….

Primary Care Corner with Geoffrey Modest MD: Rivaroxaban and Increased Intracranial Hemorrhage vs. Dabigatran

6 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent review compared the adverse effects of dabigatran and rivaroxaban, two of the NOACs (non-vitamin K antagonist oral anticoagulants) –see doi:10.1001/jamainternmed.2016.5954. This follows another report finding increased bleeding risks as well as MIs in post marketing case reports for dabigatran following its approval. This new report, funded by Medicare and the FDA, did find a significant increase in major bleeds from rivaroxaban over dabigatran.

Details:

  • Retrospective new-user cohort study of 118,891 patients with nonvalvular atrial fibrillation who were 65 years or older and enrolled in Medicare from 2011 to 2014. Patients were included if they had a diagnosis of atrial fibrillation or flutter and filled a first prescription for either drug in this time period. Excluded if they had less than six months of enrollment in Medicare, were younger than 65, were in a skilled nursing facility or nursing home.
  • 52,240 were on dabigatran and 66,651 were on rivaroxaban
  • 50% were 65 to 74-year-old/40% were 75 to 84-year-old, 47% female, 91% white/4% black, 33% with diabetes, 40% hyperlipidemia, 86% hypertension, 15% obese, 19% smoking, 15% with heart failure, 33% with CHADS2 score of 0 to 1, 40% with score of 2, 19% with score of 3; 10% with HAS-BLED score of 1, 54% score of 2, 29% score of 3.

Results:

  • 2537 had a primary outcome of thromboembolic stroke (n=306), intracranial hemorrhage (176), or major extracranial bleeding (1209) including major GI bleeding (1018) and mortality (846).
  • Rivaroxaban vs. dabigatran was associated with:
    • 19% reduction in thromboembolic stroke, HR= 0.81 (0.65 to 1.01). Nonsignificant. This translates to 1.8 fewer cases of thromboembolic stroke per 1000 person-years
    • 65% increase in intracranial hemorrhage, HR 1.65 (1.20 to 2.26).  AIRD (adjusted incidence rate difference): 2.3 excess cases per 1000 person-years
    • 48% increase in major extracranial bleeding, HR 1.48 (1.32 to 1.67). AIRD = 13.0 excess cases per 1000 person-years; including 40% increase in major gastrointestinal bleeding, HR 1.40 (1.23 to 1.59). AIRD of 9.4 excess cases per 1000 person-years
    • 15% increase in overall mortality, HR 1.15 (1.00 to 1.32), borderline significant at p=0.051, AIRD of 3.1 excess cases per 1000 person-years. In patients 75 years or older or with CHADS2 score greater than 2, the excess risk was significant (27% and 24% increases, respectively).
    • The excess rate of intracranial hemorrhage exceeded the attributed reduced rate of thromboembolic stroke (the latter actually didn’t reach statistical significance)

Commentary:

  • As I have mentioned in several prior blogs, I am very concerned about the widespread adoption and use of NOACs in non-valvular atrial fibrillation. I believe there was significant drug company malfeasance in both the design and presentation of the data. See blogs referenced at the end for more information. This is not to say that NOACs are decidedly bad, just that the studies on which their approval were based were seriously flawed, perhaps largely because of the drug company cover-ups.
  • As a point of reference, in a large meta-analysis of warfarin in patients with a fib, intracranial hemorrhage occurred in 6 patients on warfarin vs. 3 on control, with n= 2900); and extracranial hemorrhage with warfarin was less than 0.3% per year(see Hart RG. Ann Intern Med 2007; 146:857).
  • It was interesting that more cardiologists prescribed rivaroxaban than family practitioners. Not sure what this reflects. Sensitivity analysis did not show that the patients on rivaroxaban were sicker. Perhaps the cardiologists were aware of the post marketing studies on the harms of dabigatran. Perhaps they were more influenced by the ROCKET-AF study of rivaroxaban(which has been criticized for using defective INR machines, see blogs and NEWS FLASH below). It is important to note that there are no head-to-head comparisons of these different NOAC medications
  • It is perhaps significant that the curves for intracranial hemorrhage, major GI bleeding, and mortality diverged during the follow-up period, though there was convergence on the event rate for thromboembolic strokes (i.e.: increasing problems without increasing benefits).
  • One wonders if some of the increased incidence of bleeding with rivaroxaban is that it actually has the same half-life as dabigatran of about 12 hours, but is dosed at once a day, whereas dabigatran is dosed twice a day
  • The study is limited by several factors. It is a retrospective analysis, and cannot have the rigor of the conclusions of a well conducted randomized trial. Also the mean duration of on treatment follow-up was only four months, though they did have a reasonable representation of those on meds at least 6 to 8 months.
  • So, to me this huge acceptance of NOACs over warfarin (which certainly has its well-known drawbacks) seems more to reflect drug company shenanigans and heavy-duty marketing than clear benefit, and with attendant risks (though i have occasionally prescribed them, e.g. when patients were spending long periods of time in other countries without access to INR monitoring).

For blogs on NOACs, best to go to http://blogs.bmj.com/ebm/category/vte/, which has blogs on the rivaroxaban study (ROCKET-AF) using  defective INR machines in those patients on warfarin, a huge Swedish study showing safety and efficacy of warfarin when patients were mostly in the appropriate therapeutic range, and a slew of articles on drug company malfeasance in promoting dabigatran when internal drug company memos for example showed that they knew that drug levels actually should be monitored (though this went against their main selling point: that one would not have to  monitor levels vs warfarin), as well as the study mentioned above about post-marketing serious adverse events of dabigatran, with the comment that “the Institute for Safe Medication Practices reported that dabigatran was responsible for more serious adverse events than 98.7% of all medications” [and it seems to be better than rivaroxaban, at least by the above study!!!!!]. I also continue to be concerned about the lack of easy access to reversal agents for the NOACs, especially in smaller hospitals outside of large academic centers.

*********NEWS FLASH********

  • There was a new investigative report by Deborah Cohen in BMJ last week (she seems to have spear-headed many of the really great reports in BMJ about drug company malfeasance), stating that the drug company (Janssen) actually knew that the INR testing devices were faulty in the ROCKET AF study (which single-handedly propelled rivaroxaban into blockbuster status), yet withheld this information from the FDA. It turns out that the increased intracranial bleeding with warfarin might have been related to the fact that 33% of actual laboratory readings of INR were above 4, yet the defective point-of-care machines gave an INR on the same sample of between 2-3 (see doi: 10.1136/bmj.i5131)

Primary Care Corner with Geoffrey Modest MD: ACE Inhibs Decrease Conduction System Disease

11 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A secondary analysis of the ALLHAT hypertension study (see doi:10.1001/jamainternmed.2016.2502 ) found that patients in the lisinopril arm had decreased development of cardiac conduction system disease, which the authors suggested was due to lisinopril’s anti-inflammatory and antifibrotic properties.

Details:

  • ALLHAT was a community-focused hypertension study in 623 North American sites with 3 medication arms: lisinopril, amlodipine, and chlorthalidone. There was also a lipid component, and patients with fasting LDL 120-189 mg/dl (or 100-129 if known atherosclerosis) were randomized to pravastatin vs placebo. Follow-up 5 years
  • 21,004 people: 56% men, mean age 66.5, 92% white/6% black, baseline BP=174/98, BMI 28, Framingham risk score 22%, 16% smokers

Results:

  • 1114 developed conduction system disease: LBBB in 389, RBBB in 570, intraventricular conduction delay in 155
  • lisinopril vs chlorthalidone: 19% reduction in developing conduction system disease [HR 0.81 (0.69-0.95, p=0.01] with lisinopril
  • Amlodipine was non-significantly different from lisinopril

Commentary:

  • It was interesting that in this study no one developed lesser conduction system abnormalities such as 1st degree AV block, LAFB, or incomplete RBBB, which suggests that there might be a different pathophysiology than simply a progression of conduction system dysfunction (e.g. progressive fibrosis of Lev). The data on progression of 1stdegree AV block, for example, are mixed, with some long term studies finding this to be a benign condition, but some studies (e.g. Framingham Study) did find that an increase in atrial fibrillation (HR 2.1), likelihood of progression to require a pacemaker (HR 2.9) and higher all-cause mortality (HR 1.4): see Cheng S. JAMA 2009; 301(24): 2571.
  • LBBB and RBBB are clearly associated with increased cardiac mortality, as well as the potential progression to complete heart block
  • Lisinopril was better than chlorthalidone in this secondary analysis, controlling for an array of clinical variables, including demographics, BMI, smoking, aspirin use, diabetes, CAD, LVH, lipids. And this wasdespite the fact that the achieved blood pressure reduction was inferior with lisinopril.
  • Concerns about the study:
    • This is a secondary analysis, and there was some selection bias (those who received serial EKGs were more likely to be men and white, not have diabetes, and to be on aspirin)
    • >40% of all  participants were on at least one additional step 2 or step 3 drug, which brings up 2 issues:
      • The choice of the second and third agents was prescribed (either atenolol, clonidine or reserpine as step 2, hydralazine as step 3) and these were not standard community practice even at that time, at least in the Boston area (e.g.: adding atenolol to lisinopril was not done much then, since that combo was felt to be less synergistic, both being renin-active agents. The other agents were not used much at all)
      • There were no granular data presented separating out patients just on lisinopril as a single agent vs those on lisinopril in combination. This is problematic if lisinopril plus one of the second line meds did have some synergistic effect in combination for preventing conduction system abnormalities. So, for example, maybe the lisinopril did nothing alone, but did so only in combination with another med. in that case the conclusion that lisinopril is good for protecting the conduction system would be erroneous.
    • If lisinopril were protective, why would that be the case?
      • I think positing the anti-inflammatory effect is a bit of a stretch, since those on pravastatin (a pretty potent anti-inflammatory) had no protection and in fact a trend to worse conduction system disease outcomes
      • Clearly the issue is not lowering the blood pressure per se, since the lisinopril group had less BP improvement
      • My guess is that the issue was decreasing LVH, since LVH was the strongest single predictor of incident conduction system disease in multivariate analysis. (The association with lisinopril above did control for LVH, but only LVH at baseline. And only by the relatively poorly sensitive EKG). And, ACE inhibitors/ARBs are the best agents for reversing LVH. Also, LVH itself does have significant mortality associated with it, which is decreased when an antihypertensive agent decreases EKG-determined LVH (see the LIFE trial, Dahlof B. Lancet 2002; 359: 995, which showed that the ARB losartan was better than atenolol in decreasing cardiac events, but that with LVH regression by either drug, there were fewer cardiac events – i.e., it was the LVH regression that mattered, not the drug. unfortunately, they did not report on conduction system dysfunction). The data on reversal of LVH is almost as good for calcium blockers (e.g. amlodipine) as with ACE inhibitors (e.g. lisinopril). Diuretics (like chlorthalidone) are significantly less likely to reverse LVH.
    • So, my conclusions:
      • This study reinforces my use of dihydropyridine calcium channel blockers as my first drug for hypertensive patients. As mentioned in several prior blogs, I am concerned with using hydrochlorothiazide as the initial agent (the most commonly used one), since its durability over 24 hours is quite limited (see blog below), and this ALLHAT secondary analysis reinforces not using a diuretic. Amlodipine has a much longer duration of action and has much less blood pressure variability (perhaps an additional clinical benefit). This was pretty much the conclusion of NICE, in their 2011 analysis, suggesting that all Afro-Caribbean hypertensive individuals and all white people >55yo have a calcium channel blocker as the first agent. They do suggest an ACE inhibitor if white and <55yo (mostly because of the higher likelihood of high renin hypertension in this  group), though they also supported using chlorthalidone (but not hydrochlorothiazide)
      • And, as in the LIFE study, the current study does support preferentially using an ACE inhibitor or ARB for those with LVH by EKG (and, I would extend this to echo LVH). Though, again, amlodipine (or other dihydropyridine calcium channel blockers) are also reasonable. (i.e., the 2011 NICE guidelines are basically upheld by this study….)

 

See http://blogs.bmj.com/ebm/2016/05/04/primary-care-corner-with-geoffrey-modest-md-chlorthalidone-is-better-than-hctz-for-hypertension/ which showed that HCTZ has poor 24-hr duration, with chlorthalidone being much better

Primary Care Corner with Geoffrey Modest MD: Warfarin in Nonvalvular Atrial Fibrillation

13 May, 16 | by EBM

By Dr. Geoffrey Modest

Over the years, I have sent out several blogs about the drug company shenanigans/malfeasance in studies promoting NOACs (non-vitamin K antagonist oral anticoagulants) — See link at bottom. Here is a large study suggesting the benefits of warfarin (See doi:10.1001/jamacardio.2016.0199 ). The authors note that studies finding NOAC superiority were in comparison to warfarin where the times-in-therapeutic range (TTR) varied from 55.2% to 64.9%. In the current study researchers looked at the relative effectiveness of warfarin for patients with atrial fibrillation (AF) as it varied with TTR. Data are from a large Swedish registry.

Details:

  • Retrospective, multicenter cohort study of 40,449 patients
  • 40% women, mean age 73, mean CHA2DS2-VASc (see below) score 3.3, TTR<70% in 43%, hypertension 60%, heart failure 30%, renal failure 4%, excessive alcohol use 2%, history of falls 8%, prior major bleed 6%, MI 21%, diabetes 18%, stroke 19%, TIA 8%
  • 4311 patients also on aspirin with the warfarin, with the concomitant diseases/risk factors about the same as the overall cohort except that 43% had a prior MI (vs 17% just on warfarin)

Results:

  • Annual all-cause mortality 2.19% (2.07-2.31), intracranial bleed 0.44% (0.39-0.49)
  • Comparing those with TTR <70% vs >70% (all are annual rates)
    • All-cause mortality was 4.35% vs 1.29%
    • Any major bleed was 3.81 vs 1.61%, with intracranial bleed 0.72 vs 0.34%; GI bleed 1.26 vs 0.56%
    • Any thromboembolism was 4.41 vs 2.37%, MI 1.90 vs 0.98%, venous thromboembolism (VTE) 0.24 vs 0.09%, and arterial embolism 2.52 vs 1.41% [thromboembolism defined as: stroke, TIA, peripheral arterial emboli, venous thromboembolism, MI]
  • The role of INR variability (dividing those around the median of higher vs lower variability in their cohort): comparing high vs low
    • All-cause mortality was 2.94% vs 1.50%
    • Any major bleed was 3.04 vs 1.47%, with intracranial bleed 0.51 vs 0.38%; GI bleed 1.05 vs 0.50%
    • Any thromboembolism was 3.48 vs 2.46%, with MI 1.53 vs 0.96%, VTE 0.16 vs 0.11%, and arterial embolism 1.98 vs 1.51%
  • For those with TTR >70%, INR variability did not matter
  • For those on aspirin
    • All-cause mortality was 2.57% vs 2.13%
    • Any major bleed was 3.07 vs 2.04%, with intracranial bleed 0.62 vs 0.41%; GI bleed 1.16 vs 0.67%
    • Any thromboembolism was 4.90 vs 2.12%, with MI 1.53 vs 0.96%, VTE 0.19 vs 0.12%, and arterial embolism 2.72 vs 1.54%
  • For those with renal failure, intracranial bleed more than twice as common, with HR 2.25 (1.32-3.82)
  • The strongest predictor of intracranial bleeding was renal failure

So, a few issues:

  • These data, though not from a prospective, randomized study, do reflect more of a real-world community setting.
  • The results for patients in good control (TTR>70%) is actually better than in the “pivotal NOAC studies”.
  • In terms of the issue of using the combo of warfarin and aspirin:
    • I am very concerned about the increased serious adverse events with this combination (see http://blogs.bmj.com/ebm/2014/11/20/primary-care-corner-with-geoffrey-modest-md-aspirin-plus-warfarin-for-afib-and-cad/ , which looks at several observational studies on aspirin plus warfarin for patients with AF and CAD, all showing much higher risks (e.g., bleeding) without any clear benefit. The PREFER trial (see De Caterina, R. Heart 2014; 100: 1625) looked at a large European registry of patients with AF and found that 95% of those on dual antiplatelet and anticoagulation therapy did NOT have an “accepted indication” (i.e.: acute coronary syndrome or stenting –and, this is the current recommendation of the European Society of Cardiology guidelines in AF: anticoagulant therapy only except in these indications).
    • In the above Swedish study, only 2.6% of those on additional aspirin had a clear indication for this therapy. And this study really supported NOT using aspirin, given the higher mortality, higher MI/VTE/arterial embolism, and much higher bleeding risk (though, as noted, this was not an RCT, had many more patients with prior MI, so it is not so surprising that there was an increase in these thrombotic events. But twice the level of major bleeds???  And 50% more thrombotic events??? Is aspirin really useful?? I personally have stopped aspirin in my patients on warfarin, based on the prior blog)
  • So, my bottom line: this Swedish study confirms the utility of warfarin in patients with nonvalvular AF, though clearly differentiates its advantages in those in good control (INR in range >70% of the time) vs not. I do have trouble with the NOACs overall, given the noted drug company issues in my prior blogs and the lingering concern that if they are in an accident, reversal agents are not widely available. But I have occasionally used NOACs in patients who are leaving the country and cannot get their INR checked, or it is just too difficult to get the INR in range despite best efforts all around, often including home-based nursing care/checking the INR at home. That being said, the clear majority of my patients on warfarin are definitely in the >70% TTR category and seem to be doing just fine…. (though I do need to monitor them frequently, but, then again, most of them have significant cardiac and other morbidities, and my guess is that the increased monitoring/health system contact is actually a positive thing)

CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 75 years [doubled], diabetes mellitus, stroke [doubled]–vascular disease, age 65-74 years, and sex category [female])

For older blogs, see: http://blogs.bmj.com/ebm/2016/01/19/primary-care-corner-with-geoffrey-modest-md-antithrombotic-therapy-guidelines/ goes through the antithrombotic therapy guidelines but also reviews the history of drug company malfeasance with the NOACs, which really make me uneasy about using them…

Primary Care Corner with Geoffrey Modest MD: Atrial Fibrillation and Lower BP

24 Mar, 16 | by EBM

By Dr. Geoffrey Modest

Although there have been many studies confirming a role of hypertension in the development of atrial fibrillation (AF), a secondary analysis of the LIFE trial gives insight into the effects of achieving different levels of blood pressure on the frequency of development of AF (see Hypertension. 2015;66:368). The LIFE trial (Lancet. 2002;359:99) used 2 different hypertensive agents (losartan and atenolol) in patients with EKG-documented LVH to assess differences in clinical outcomes.

Details:

  • 8831 hypertensive patients (mean age 66.6, 45% male, 6% Black race, 13% with diabetes, 18% ischemic heart disease, 7% MI, 5% stroke, 15% smokers, BMI 28), with EKG LVH and no history of AF, in sinus rhythm on baseline EKG, were randomly assigned to losartan or atenolol, and followed 4.6 years
  • Patients with in-treatment achieved SBP ≤ 130 mmHg (lowest quintile at last measurement in the study) were compared to those with SBP 131-141 vs those with ≥​142

Results:

  • New onset AF developed in 701 patients (7.9%)
  • In multivariate analyses (controlling for age, sex, race, DM, history ischemic heart disease/MI/heart failure, serum glucose/creatinine/microalbumin, prior BP therapy), comparing achieved SBP of ≥​142 mmmHg:
    • Achieved SBP of ≤​130 mmHg was associated with a 40% lower risk of AF (18-55%, p=0.001)
    • Achieved SBP of 131-141 mmHg was associated with a 24% lower risk of AF (7-38%,  p=0.007)
  • ​For each 10mmHg decrease in SBP:  13% lower risk of AF (9-17%, p<0.001)
  • ​And, no difference in benefit of lower SBPand AF in those > or <60yo
  • But, lowering SBP to ≤125 mmHg was no longer associated with reduced risk of AF (all achieved SBPs less than 125 were nonsignificantly related to the development of AF, though the hazards ratio trended to increasing risk with progressively lower SBP)

So, a few points:

  • Although the LIFE cohort included only patients with LVH on EKG, it has the advantage of using 2 different BP meds with 2 different mechanisms of actions. This makes it more likely that it is the achieved blood pressure which correlated with the development of AF. (With only one medication, one might wonder if the association was the blood pressure lowering effect or perhaps some other unrelated effect of the med).
  • But, one concern here is that those on losartan had somewhat lower likelihood of developing AF (in those who developed AF, 46.2% were on losartan vs 50.6% on atenolol). And we know from the LIFE study that those on losartan had more regression of their LVH than those on atenolol, and this was the purported reason that in the overall LIFE trial there were overall fewer cardiac events in the losartan group. In fact, the incidence of cardiac events in the LIFE study overall was equivalently lower in both the losartan and atenolol groups when there was regression of LVH, but regression was more common in the losartan group. So, it may be that looking at the post-hoc analysis of hypertensive patients with LVH and their likelihood of developing AF might not be so generalizable to hypertensives without LVH (.e., if the development of AF were at least partly related to LVH on EKG).
  • Prior articles have had somewhat mixed results: the Cardio-Sis trial (Lancet. 2009;374:525) found statistically fewer cases of new onset AF in those on tighter control (achieved SBP of 131.9 mmHg was better than 135.6), though another study did not (Am J Hypertens. 2008;21:1111)
  • So, this trial adds to the argument that more dramatic lowering of the blood pressure may have another positive effect: decreasing the likelihood of developing AF. And, of course, this is a really important clinical endpoint (stroke, other emboli, risks of prolonged anticoagulation and/or cardiac procedures, risk of sudden cardiac death and heart failure, risk of cognitive decline, …). though there were also limitations of the SPRINT trial (see http://blogs.bmj.com/ebm/2015/11/19/primary-care-corner-with-geoffrey-modest-md-tighter-blood-pressure-control-the-sprint-trial/​ , which did not include diabetics but did find a pretty much all-endpoint benefit of tighter control at an achieved SBP of 121 mmHg), this current study does add to the literature suggesting more aggressive goals of therapy, with SBP target in the 125-130 mmHg range, at least in those with EKG-LVH. Though, it should be added, that this study had too few diabetics to make a meaningful argument about their blood pressure goal, and another recent blog (see http://blogs.bmj.com/ebm/2016/03/07/primary-care-corner-with-geoffrey-modest-md-hypertension-goal-in-diabetes/ ) assessed a systematic review finding that the goal for diabetics should perhaps be higher than others, with a target of 140/75-80. And I will add my usual caveat to be less aggressive with elderly, since postural hypotension/risk of falls is so common(?autonomic dysfunction, see http://blogs.bmj.com/ebm/2014/12/18/primary-care-corner-with-geoffrey-modest-md-orthostatic-hypotension/) and too low a blood pressure can be associated with cognitive decline (see http://blogs.bmj.com/ebm/2015/04/23/primary-care-corner-with-geoffrey-modest-md-too-low-blood-pressure-and-cognitive-decline-in-elderly/ ).

Primary Care Corner with Geoffrey Modest MD: Rivaroxaban, Is It Really Better Than Warfarin for Non-valvular Atrial Fib?

16 Feb, 16 | by EBM

By Dr. Geoffrey Modest

The BMJ spotlight team (actually Deborah Cohen, associate editor) just released another investigation into poorly-regulated drug-company-supported studies which have led to large changes in clinical practice and large profits for drug companies (see BMJ 2016;352:i575). This one is a challenge to the ROCKET-AF study (see N Engl J Med 2011;365:883-91), which was the single study leading to FDA approval for rivaroxaban, a​ direct thrombin inhibitor, by showing that although it was as good as warfarin in patients with non-valvular atrial fibrillation in preventing strokes, there were fewer episodes of intracranial and fatal bleeds. Of note, rivaroxaban is now the world’s best-selling new anticoagulant. However, it turns out that the ROCKET-AF study relied on defective point-of-care INR machines which gave falsely low INR levels, thereby leading the researchers to increase the warfarin dosing and perhaps predisposing patients to more bleeding.

Details:

  • BMJ found that the INR devices used had been recalled in December 2014 because the FDA issued their highest level recall notice finding that these devices could give “clinically significantly lower” INR values. The device manufacturer Alere had received 18,924 reports of malfunction and 14 serious injuries, dating back to 2002 (prior to the ROCKET-AF trial starting)
  • September 2015: BMJ asked ROCKET investigators about the device recall. No direct response, just one from the drug company that they were unaware of the recall.
  • The European Medicines Agency (EMA, the European equivalent of the FDA) in April 2015 did not know these devices were used in the ROCKET-AF study, and called for an independent investigation into direct oral anticoagulants. The company claimed that the results of ROCKET-AF were still valid after conducting some sensitivity analyses. No independent investigation has happened to date.
  • But, as per Harlan Krumholz, a cardiologist at Yale, “the study should be considered of uncertain validity until a more thorough review can be  done”, and to have “an investigation by an independent group of experts to quickly determine if there are grounds for retraction [of the study]”.
  • In looking back at the original FDA approval for rivaroxaban, 2 primary reviewers had expressed concern about the warfarin control and recommended that the drug not be approved, stating “ROCKET provides inadequate information to assess the relative safety and efficacy of [rivaroxaban] in patients whose warfarin administration can be well-controlled”
  • BMJ asked the ROCKET researchers if those patients who had major bleeds had had laboratory INRs checked. None responded.
  • It turns out that at the 12-week and 24-week time-periods, there were simultaneous measurements of INR by device and a central lab, though this data has not been released.
  • There was a rebuttal by the investigators to the above BMJ charges (see DOI: 10.1056/NEJMc1515842). The investigators did post-hoc analyses using the FDA recall criteria [medical conditions that the FDA thought might lower the INR value of the device: anemia with hematocrit >30%, and conditions which raised fibrinogen levels (acute inflammation, chronic inflammatory conditions, severe infection, cancer or end-stage renal disease]. Results of the post-hoc analysis were mixed:
    • ​In those without recall conditions: no significant difference in strokes with rivaroxaban vs warfarin; more intracranial hemorrhages, fatal or critical organ bleeding with warfarin; more GI bleeding overall with rivaroxaban
    • In those with recall conditions (and presumably on unnecessarily higher doses of warfarin): decreased stroke in those on rivaroxaban but only in the per-protocol patients; no difference in intracranial hemorrhages, fatal/critical organ bleeding; more GI bleeding with rivaroxaban.

So, these articles bring up several issues:

  • It is a little unsettling to me that rivaroxaban was approved based on only one drug company-sponsored study
  • I’m not sure what to make of the post-hoc analysis by the investigators. Surprisingly, they seem to show fewer adverse events in those without the FDA-designated recall conditions, though interestingly in those patients with those conditions, rivaroxaban​seemed a bit worse on clinical bleeding. But are those recall conditions complete? Many older studies, for example, found a relationship between smoking and high fibrinogen levels (to the point that many posited that the main mechanism of smoking causing heart disease was mediated by fibrinogen, and that stopping smoking quickly reversed much of the increased CAD risk because smoking’s effect on fibrinogen levels reversed so quickly). Smoking was not on the recall list. Are there other unknown conditions which lead to aberrancies in the device INRs?Or are there other unknown biases which can happen in a post-hoc analysis? It would be interesting to know the relationship between the laboratory INR measurements at the 12 and 24-week times and the results of the point-of-care devices. And what the correlation was on an individual basis between these discrepancies and the positive and negative clinical outcomes. And, I would strongly support an independent review.
  • A prior BMJ issue and several other studies have suggested that dabigatran also may have many more adverse events than reported and that there were drug company shenanigans; in particular the drug company covered up evidence suggesting that there needed to be blood monitoring, despite the main selling point for the drug being that no drug monitoring was necessary, as opposed to warfarin and the need to follow INRs, (see  http://blogs.bmj.com/ebm/2016/01/19/primary-care-corner-with-geoffrey-modest-md-antithrombotic-therapy-guidelines/). As a result of the BMJ and other articles about dabigratan, at the end of 2015 both the EMA and FDA held meetings to see if there was a need to monitor blood levels of direct anticoagulants and adjust the dose as necessary to maximize benefits/minimize harms.
  • This raises the issue that the FDA historically has been less aggressive in regulating devices than meds. Typically, once one device is accepted, there is much less overview on similar products (new devices just need to be “substantially equivalent” or similar to ones already on the market). And, the issue of rivaroxaban highlights that approval of meds may well require studies using not-so-well-regulated devices which could potentially dramatically affect the results. And, this is compounded by the selection bias favoring the drugs: positive studies of drugs are published at a much higher rate than negative studies. And once a drug company has a positive study (as with ROCKET-AF), there is little incentive to do further confirmatory studies after a drug is approved.
  • So, yet again, I am very hesitant to prescribe these newer meds, given huge conflicts-of-interest, the large numbers of cases of drug companies hiding results they do not like, the decreasing authority and efficacy of the FDA in monitoring new drugs (e.g., see http://blogs.bmj.com/ebm/2015/09/10/primary-care-corner-with-geoffrey-modest-md-snake-oil/ ), and the increasing reliance on post-marketing surveillance, which seems to happen only pretty rarely (e.g., see http://blogs.bmj.com/ebm/2015/12/26/primary-care-corner-with-geoffrey-modest-md-the-drug-co-shenanigans-reach-new-heights/ ). I continue to use warfarin as my preferred anticoagulant, and I use the close monitoring of INRs (which in rock stable patients, can actually be done on an every 2-3 month basis) as a means to check-in with these patients, who are typically medically-complex anyway.

Primary Care Corner with Geoffrey Modest MD: 3 Heart Failure Articles of Note

20 Jan, 16 | by EBM

By Dr. Geoffrey Modest

There were 3 useful articles in the JACC-Heart Failure journal which I think are useful in primary care

  1. This article (see doi.org/10.1016/j.jchf.2015.09.002​) looked at the target for b-blocker (BB) use in patients with heart failure and reduced ejection fraction (EF, <35%) within the HF-ACTION study, the largest trial of BB use involving 2331 medically stable outpatients and showing benefit from a structured aerobic exercise program over 2.5 years (see JAMA 2009; 301(14): 1439). The issue addressed is titration of the BB dose: the HF-ACTION and other trials have found that just lowering the heart rate (HR) improves mortality but raise the question of whether that explains the full BB effect, or is the achieved dose of the BB more important.

Details:

  • 2320 patients (mean age 60, 28% female, 32% black, BMI 30, 62% NYHA Class II, 50% ischemic cardiomyopathy, EF 25%, SBP 110 mmHg, resting HR 70, 80% in sinus rhythm).
  • Divided into 2 groups: those on high dose carvedilol (>=25mg/d) vs low dose (<25 mg/d); and those with high heart rate (>=70 bpm) vs low (<70 bpm)

Results:

  • All-cause death or all-cause rehospitalization (all with adjusted HR values)
    • High vs low dose BB, hazard ratio 0.87 (0.77-0.99), p=0.03, i.e. 13% decrease in deaths/hospitalizations
    • High vs low HR, hazard ratio 11 (0.98-1.24), p=0.09, nonsignificant
    • And looking at the combination, adding HR to the analysis added no significant value
  • There was a significant 21% decrease in all-cause death as well as a 23% decrease in cardiovascular death or heart failure rehospitalization with high-dose BB. HR was not significant for any of the outcomes in either unadjusted or adjusted analyses. Part of the reason for the lack of significance is the relatively low number of events, under powering the study.
  • The association between BB dose and the above clinical outcomes was independent of the baseline HR
  • There was no significant difference in the biomarker NT-proBNP between these groups, though there was more of a decrease in the biomarker in the high BB dose group, though nonsignificant. Related to small numbers?

So, this study reinforces maximizing the BB dosage, even in those with HR<70bpm. I’m not sure what the BP was for this group (not reported), but the high numbers of patients in the community not on optimal BB doses (in the 80-90% range!!) reflect perhaps a less aggressive approach to therapy than seems warranted. I should add the caveat that this is a post-hoc analysis, and as such is potentially limited by confounding.

 

  1. A meta-analysis of 11 studies looking at the progression of asymptomatic heart failure (HF) to symptomatic HF, over an average of 7.9 years (see org/10.1016/j.jchf.2015.09.015), assessing both those with ALVSD (asymptomatic left ventricular systolic dysfunction), and ALVDD (asymptomatic left ventricular diastolic dysfunction).

Details:

  • 11 studies identified with 5,369 patients. 5 with ALVSD, 3 with ALVDD, and 4 with both
  • ALVSD somewhat variably defined, but typically ejection fraction (EF)<30-50%

Results:

  • ALVSD: absolute risk of progression to symptomatic HF was 8.4/100 person-years (4.0-12.8 per 100 person-years); adjusted relative risk was 4.6 (2.2-9.8)
  • ​ALVDD: absolute risk of progression to symptomatic HF was 2.8/100 person-years (1.9-3.7 per 100 person-years); adjusted relative risk was 1.7 (1.3-2.2)
  • In controls (no ventricular dysfunction): absolute risk of progression to symptomatic HF was 1.04/100 person-years (0.0-2.2 per 100 person-years)
  • ​Per a 1-SD change in EF, there is an overall 38% increased risk of developing clinical HF [RR=1.38 (1.14-1.67]
  • The main predictors of progression were: age, sex, blood pressure, diabetes, and BMI

So, it is pretty clear that asymptomatic LV dysfunction is associated with a significant risk of becoming symptomatic, more so in those with reduced systolic function, and with increasing risk as the EF decreases. Studies have shown that asymptomatic LV dysfunction is also associated with reduced survival, and interventions as with ACE inhibitors prevent or delay the development of symptomatic HF and decreases mortality.

 

  1. Looking at the CIBIS-ELD trial (Cardiac Insufficiency Bisoprolol Study in Elderly), researchers assessed the tolerability and efficacy of bisoprolol vs. carvedilol in symptomatic (at least NYHA class 2) patients > 65 yo with either HFrEF (heart failure with reduced ejection fraction) or HFpEF (heart failure with preserved EF) — doi.org/10.1016/j.jchf.2015.10.008​.

Details:

  • 626 patients with HFrEF (mean age 73, 26% women, 61% NYHA class 2/32% class 3, 15% with peripheral edema, mean HR 75, mean BP 134/80, BMI 27, EF 35%, NT-proBNP 968; CAD in 68%, dilated cardiomyopathy in 19%, hypertension in 80%, 9% smokers, 48% with MI) and 250 with HFpEF (mean age 73, 66% women, 76% NYHA class 2/23% class 3, 35% with peripheral edema, mean HR 71, mean BP 146/80, BMI 29, EF 59%, NT-proBNP 253; CAD in 33%, dilated cardiomyop in 2%, hypertension in 90%, 8% smokers, 18% with MI) were randomized to bisoprolol vs carvedilol, with a goal to up-titrate to the target or maximally tolerated dose
  • Carvedilol started at 6.25mg bid with target of 25 mg bid (or 50mg bid in those with body weight >85kg); bisoprolol was 2.5mg daily with target of 10mg daily, with biweekly dose doubling
  • Titration was to be over 6 weeks (8 weeks for those >85kg and on 50mg carvediol), then 4 week maintenance period

Results:

  • Mean daily dose of bisoprolol after titration was 4.93 mg in the HFpEF and 5.01 in HFrEF groups; for carvedilol it was 25.3 and 29.1 respectively) — nonsignificant differences (19% of HFpEF vs 27% with HPrEF reached target dose, regardless of treatment group, which was significant)
  • ​It took longer to uptitrate those with preserved EF (12%) vs reduced EF (5%)
  • Similar HR reductions, at 7 bpm in both those with preserved and reduced EFs. BP decreased more with the preserved EF group (14/5 mmHg) vs reduced (8/4)
  • NYHA functional class improvement:
    • Reduced EF group had 34% improvement vs preserved EF group (decrease of 31% vs 18%): 23% improvement (p<0.001  for comparison), and no diff if on carvedilol vs bisoprolol
  • 6-minute walk distances and physical quality of life measures improved in the HFrEF group but no change in HFpEF groups (20 vs 4 meters).
  • In 3 measures of quality of life (SF-36 PFS, SF-36 PCS and SF-36 MCS, reflecting physical functioning, physical component, and mental component): there was only a significant change in the HFrEF group only
  • ​Echo for systolic function: mean EF improved in those with reduced EF from 35% to 39% by week 12, no change in the preserved group.
  • ​Echo for diastolic function: mean E/e’ and left atrial volume index not change in either group, but E/A mitral flow did increase in those with preserved EF [i.e., BBs did not change any markers of diastolic function in either those with preserved or reduced EF), and no difference between the BBs]
  • ​Adverse effects: more in HFpEF patients (79%) vs HFrEF (58%), with p<0.001 for difference, mostly bradycardia (20% vs 11%), dizziness (15% vs 4%), and fatigue (18% vs 4%)

So, one of the major conundrums in treating HF is that about 50% have HFpEF (preserved EF), with increasing prevalence over time. This group in general has the same overall prognosis as those with reduced EF. And we have minimally effective treatments as compared with those with reduced EF. On the surface, BBs would seem to be reasonable drugs (they decrease BP, decrease LVH, decrease HR, and decrease ventricular arrhythmias — a leading cause of death in this group). This study did not find any really significant differences between using bisoprolol vs carvedilol, either in tolerability or efficacy. But there were real differences between those with reduced EF (easier ability to titrate dose up, more improvement in NYHA functional class and measures of quality of life, walking distance, EF, fewer adverse events) and much less in those with preserved EF (more decrease in HR, BP, and no real clinical improvement). This was a short-term study, and without a placebo group,

—–

So, why do I bring up these 3 articles?

  • HF is really common (5.7 million US adults, lifetime risk in a young adult being 20%), has a substantial morbidity/mortality, and there are lots of people with asymptomatic HF (3-4x the number with symptomatic).
  • The first article found that for those with reduced EF, trying to push BB to the targeted dose (which, unfortunately, does not happen so often in community practice), seems to confer the most benefit
    • The treatment algorithm is pretty straightforward (diuretics as needed, then ACE/ARB, then BB, then aldosterone antagonists; though can use hydralazine/isosorbide dinitrate in African-Americans and those not tolerant of ACE/ARBs), but these meds all lower blood pressure, and in my experience the not-so-uncommon limiting factor is that the blood pressure can’t abide this many agents at full dose, leaving us some unanswered questions:
      • What are the priority agents (in general the studies have assumed this medication order, but if the blood pressure is low, which individual agent is the most effective?)
      • Is it better to have low doses of multiple agents vs maxing out the meds in a specific order (studies do suggest that low doses of meds are useful)?
    • And another issue is hyperkalemia. Though the diuretics help counter this, all the other meds make it worse. And this is especially an issue in diabetics (not-so-uncommon), where hyperkalemia is more often an issue.
      • Again, should we give a little of many agents or push individual agents in a particular order? (E.g. my experience is that BBs are less hyperkalemic than the ACE/ARB or aldo antagonists. I should add that the CIBIS III trial did find that starting BBs first seems to be equivalent in outcome to ACE/ARBs, but the advantage of ACE/ARB first is that they work faster, and BBs can cause worsening heart failure in the short-term, further supporting starting first with ACE/ARB to better optimized initial treatment)
    • The second article found that those with asymptomatic HF have a real risk of progression to symptoms, more-so in those with reduced EF (systolic dysfunction). And these asymptomatic people, a very common issue, are at much higher risk of morbidity and mortality, raising:
      • The potential possibility that we should be screening more routinely for asymptomatic LV dysfunction, then doing interventions to improve the function and potentially decrease both the likelihood of symptomatic HF and mortality. Seems like a useful study to do, since the prevalence, morbidity and mortality of HF is so profound. But at this point it is not clear that early identification and treatment changes any clinical outcomes.
      • And, it reinforces the likely benefit of preventing ventricular dysfunction in the first place: decreasing systolic dysfunction by decreasing cardiovascular risk factors, the development of nonischemic cardiomyopathies (e.g. decreasing stress, treating infections such as chagas, lyme early and aggressively, etc.); and decreasing diastolic dysfunction (also treating hypertension, stress, development of myocardial ischemia)
    • And the third article, though actually a short-term tolerability study, highlights the difficulty of treating those with preserved EF, though it should be pointed out that this was a short-term study and the mechanism of disease in those with preserved EF is different from those with reduced EF (i.e., it may take longer to reverse the cardiac remodeling in those with preserved EF)
      • ​But the bigger and more relevant/longer-termstudies do not find the same benefit with current treatment of those with preserved EF as in those with reduced EF, though there are some data that ARBs decrease hospitalizations (CHARM-Preserved trial) and that spironolactone decreases hospitalizations and (secondary analysis) deaths in those with high BNP levels (TOPCAT trial) though with a fair amount of hyperkalemia
      • In fact, treatment of those with preserved EF is pretty much several decades behind where we are with patients with reduced EF (where we were basically using loop diuretics and digoxin for symptom control, without improving mortality)
      • e., we really need better drugs (and reinforcing the above interventions to decrease the development of left ventricular dysfunction with preserved EF to the extent we can)
    • But my experience is that treating HF, esp. in those with reduced EF, is really easy to do in the primary care setting in the vast majority of patients and that there is really a very remarkable response to the meds with the above-noted algorithm (I have had several patients with shockingly low EFs in the 10-15% range who function totally normally for more than 10 years…). And we can also provide symptom control for the majority of those with preserved EF, using diuretics, ACE/ARB, ?spironolactone (which are more effective than BBs anyway in improving left ventricular size and shape), and BBs as needed to help control HR, anginal symptoms, and BP. Treating HF one of the more rewarding primary care interventions, since patients pretty regularly respond so well clinically to these interventions and feel much better so rapidly.

Primary Care Corner with Geoffrey Modest MD: Resume Anticoagulation After GI Bleed?

7 Jan, 16 | by EBM

By Dr. Geoffrey Modest

One of the many unanswered clinical questions is what to do with patients who have atrial fibrillation, are anticoagulated, but have a GI bleed. Do I just stop the anticoagulation? Should I bite my lip (but not too hard) and reinstate anticoagulation after the bleed? A recent observational study looked at this question, utilizing the great Danish clinical database (see BMJ 2015 Nov 16; 351:h5876​).

Details:

  • Danish cohort included all patients with atrial fibrillation (AF) from 1996-2012 who had a gastrointestinal (GI) bleed while on antithrombotic therapy. They then compared the patients who restarted therapy vs those who remained off therapy, beginning 90 days after the incident bleed
  • 4406 patients (mean age 78; 45% women; 24% on oral anticoagulation, 53% on antiplatelet agents, 19% on both; 25% on NSAIDs within 90 days of bleed, 15% on PPIs; 23% with prior stroke, 38% ischemic heart disease, 31% heart failure, 45% hypertensive, 20% vascular disease, 16% diabetic, 5% “alcohol misuse” as identified on admission for the GI bleed
  • Mean CHADS2 score of 2.1 (score of 1 means=moderate embolic risk, >=2 means mod-to-high risk), mean CHA2DS2-VASc score of 3.6 (score of >=2 means mod-to-high risk), mean HAS-BLED score of 2.6 (a composite of pro-bleeding factors such as hypertension, abnormal renal/liver function, labile INR, elderly, drugs/alcohol; where score >=3 means high risk of bleeding). Of note, there was really no difference in any of these scores in comparing those patients put back on oral anticoagulants or no meds. And no difference in whether they got gastroscopy or surgery, with 88% having gastric or duodenal ulcer, 12% gastritis, 2% GERD; and 5% with alcohol “misuse”, 90% on PPIs, 5% NSAIDs
  • 924 patients (27%) did not resume antithrombotic therapy (note: this is a large database study and not clear why the clinical decision was made to continue or stop therapy)

Results (I am only reporting results in those on single therapy with oral anticoagulant or antiplatelet agent):

  • In terms of absolute numbers, over a 2-year period, all-cause mortality of the whole group was really high at 40% (n=1745); thromboembolism was 12% (n=526); major bleeding was 17.7% (n=788) and recurrent GI bleed was 12.1% (n=546)
  • Comparing those who did not resume therapy with those who did:
    • For anticoagulant therapy (92% on vitamin-K antagonists):
      • All-cause mortality had HR=0.39 (0.34-0.46) – i.e. 61% reduction
      • Risk of thromboembolism had HR=0.41 (0.31-0.54) – i.e. 59% reduction
      • Risk of major bleed had HR=1.37 (1.06-1.77) – i.e. 37% increased risk, though a nonsignificant 22% increase in recurrent GI bleeds [HR=1.22(0.84-1.77)] perhaps because 90+% were on a PPI
    • For antiplatelet therapy (98% on aspirin):
      • All-cause mortality had HR=0.76 (0.68-0.86) – i.e. 24% reduction
      • Risk of thromboembolism had HR=0.76 (0.61-0.95) — also 24% reduction
      • Risk of major bleed (beginning 90 days after discharge from first bleed) had HR=1.25 (0.96-1.62 – i.e. nonsignificant 25% increased risk)
    • Subgroup analysis showed that as the CHA2DS2-VASc increased, there was associated decreased risk of all-cause mortality in those on anticoagulants (56% in those with CHA2DS2-VASc score of <2; 60% if 2-3; and 63% if >3); a HAS-BLED score >3 was associated with increased bleeding risk (41% if HAS-BLED score of <2; 64% if 2-3; and 57% if >3)
    • The single most effective change was taking patients who had been on an antithrombotic regimen (mostly aspirin) prior to the initial GI bleed and switching them to an oral anticoagulant (mostly vitamin K antagonist) after the bleed.

So, a few observations:

  • 25% of the patients with initial GI bleed were on NSAIDs. This is pretty clearly not a good thing, though hard to control completely given the easy availability of NSAIDs (I have had several patients on warfarin where I have explained the risk of NSAIDs, including naming the OTC brands, who subsequently used Advil or other OTC NSAIDs thinking they were okay. It probably is worth reiterating this message several times: by being OTC does not mean the drug is safe). Alcohol is another bleeding risk factor, which in those who drink excessively not only increases bleeding risk but also the risk of not taking anticoagulants correctly
  • I’m not sure what to make of the fact that many more of these patients were on antiplatelet agents (39% as single therapy) than anticoagulants (21% as single agents), given the high CHA2DS2-VASc scores overall (in general, the preferred therapy for those with CHA2DS2-VASc​ of 2 or more is oral anticoagulants)
  • Though they chose a waiting period of 90 days after the incident bleed to start their assessment of outcomes, there was no difference in sensitivity analysis if look at outcomes starting the day after the bleed
  • Although this was not a randomized controlled trial, there are several issues which I think make it still an important trial: this study involved a large number of patients drawn from a national registry which included all Danish residents and with linkage to pharmacy registries; there were minimal differences in the thrombotic risk (e.g. CHA2DS2-VASc score) or propensity to bleeding (HAS-BLED score) between the groups who resumed therapy and those not on therapy (i.e. no obvious selection bias); and there was a high absolute number of bad events overall and very high all-cause mortality benefit by reinstating anticoagulation. All of this suggests that there are reasonable grounds to restart oral anticoagulants, again with the proviso of trying to avoid NSAIDs and alcohol, and with close patient follow-up. Though it would be great to have a randomized controlled trial.

See http://blogs.bmj.com/ebm/category/cardiol-arrhythmia/ for many blogs on AF.

Also, another from the Danish registry looking at patients without AF but with heart failure and high CHA2DS2-VASc score, showing a high incidence of thromboembolism (see http://blogs.bmj.com/ebm/2015/09/24/primary-care-corner-with-geoffrey-modest-md-heart-failure-outcome-and-chads-vasc-risk-score-even-if-not-in-afib-2/ ).

Primary Care Corner with Geoffrey Modest MD: Atrial Fibrillation – Should We Look Harder For It?

2 Dec, 15 | by EBM

By Dr. Geoffrey Modest

Over the years, I have had several patients who have presented with significant strokes related to previously-undetected atrial fibrillation (AF). I have also had a couple of patients with dementia and no evident prior stroke, who on workup have had multiple small infarcts, again possibly related to AF. In this light, there was an interesting editorial in JAMA (see JAMA 2015; 314: 1911) ​ raising the question of whether we should be screening regularly for AF. Although not part of their argument, I think that the potential and not clearly well-defined relationship between AF and cognitive decline may be part of the incentive to screen (see below). Their argument is basically (all references are in the text):

  • AF is really common (1 in 4 lifetime risk in those >40, with 0.5% age 40, increasing to up to 15% at age 80)
  • Treatment is pretty effective: oral anticoagulation (OA) reduces stroke risk by 2/3 and mortality by 1/3, with relatively small risk of major bleeding (hence the use of pretty universal guidelines to anticoagulate if the CHA2DS2-VASc score is 2 or greater)
  • The effectiveness of OA is much more impressive than many of the other recommended screening activities/interventions
  • AF is a common cause of stroke: a recent Swedish Stroke survey of 94K patients with ischemic stroke found AF in 31K of them, which is probably an underestimate (see Stroke 2014; 45: 2599)
  • So, can asymptomatic AF be picked up by screening??
    • A systematic review found that in 123K patients, a single screen using either pulse palpation or EKG found undiagnosed AF in 1% of people overall and 1.4% of those >65yo.
    • The European Society of Cardiology 2012 guidelines on AF recommended routine checking the pulse of patients >=65 years of age, followed by an electrocardiogram as needed, for the timely detection of AF.
    • There are cheap handheld or smartphone EKG-type devices which may be useful. Preliminary studies suggest an AF pickup of 1.5-3.0%, all of whom qualified for OA.
  • Prognosis of incidental AF
    • A UK study found people with incidentally detected asymptomatic AF had stroke rate of 4% in 1.5 years and all-cause mortality of 7% in those untreated. Those on warfarin had stroke and death rates of 1% and 4% respectively
  • Cost-effectiveness
    • ​Smartphone based screening in those 65-85yo: $4066 per quality-adjusted life-year gained, $20,695 per stroke prevented (i.e., better than most preventative interventions). This age group has high incidence of AF and essentially all people >65 would qualify for OA
  • The authors suggest that we in the US follow the European guidelines and check the pulse during office visits.

So, AF has potentially devastating consequences, with significant morbidity and mortality. A few points:

  • The relationship between AF and multi-infarct dementia (MID) is not clear, and AF is not listed as a risk factor for MID by the NIH. But there was a population-based study (Rotterdam Study) which followed 6514 patients aged >55 and found a strong association between dementia and impaired cognitive function in those who developed AF and were <67 yo (see http://blogs.bmj.com/ebm/2015/10/30/primary-care-corner-with-geoffrey-modest-md-atrial-fibrillation-and-dementia/). A recent article on AF and cognition (see Stroke 2015;46:3316-3321) noted that:
    • The mechanism is unclear (?multiple small emboli, ?AF-associated cerebral hypoperfusion)– and, evidently, if the mechanism were the latter, it would be hard to attribute the cognitive decline to AF, since there would not necessarily be dectectable infarcts on brain imaging.
    • There have been meta-analyses (see Neurology 2011; 76:914, Ann Intern Med 2013; 158: 338) finding >2-fold increased risk of cognitive impairment in those with AF and subsequent stroke.
    • A few meta-analyses have found a 40% increased risk of dementia in those with AF and without stroke (see Heart Rhythm 2012; 9: 1761).
    • But, as we know, associations are not necessarily causal, and AF/dementia do have shared risk factors.
    • ​And, one of my concerns is that in many of these studies, our measurement of dementia (e.g. Mini-mental state exam) is a very blunt instrument and does not pick up subtle changes which may be very significant for the person at that time, and ultimately over years, progress to our definition of dementia.
  • Given the potential devastation of stroke/cognitive impairment, as well as the potential damage from other peripheral emboli, it seems to me that we should have a randomized controlled intervention study looking at treatment for AF and its overall effects. For that study, there would need to be some agreement on the following:
    • What is AF?  Is it a random pick-up on a routine exam (i.e., 1-minute evaluation for an irregular pulse and then followed by an EKG)? Is it a 24-hour Holter monitor, or a 30-day event monitor??? (clearly there are people with very intermittent, paroxysmal AF who have clinical emboli, and checking a pulse is going to find those with sustained AF predominantly)
    • ​What is cognitive decline? This study should include doing a more extensive evaluation for subtle cognitive decline (e.g., the Cardiovascular Health Study did look at a few instruments, including the Modified MMSE and Digit Symbol Substitution Test, as well as telephone interviews, finding those with incident AF had faster and earlier onset cognitive decline — see Neurology 2013; 81: 119).
  • But at this point, I will continue doing what I have been doing: pretty much always checking my own manual blood pressures on patients, after waiting several minutes in a reasonably relaxed atmosphere (as per prior blogs). In this setting I sometimes do pick up AF (and, by the way, the automated cuffs are pretty unreliable for blood pressure measurement in those with AF, further supporting checking manual blood pressures in those >50yo or so). But I will now add on checking the pulse for irregularities, and then follow the guidelines for treatment when I find AF. And, perhaps more aggressive assessments for AF than pulse-checking at the time of exams should be done (given the high prevalence of AF, especially in our aging population, a more intensive AF assessment such as Holter monitoring could be a very cost-effective strategy, especially given the dramatic quality-of-life issues associated with stroke/dementia). But this would need studies to determine.

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