Scrubbing Arteries for Stroke

Motivation: I made many resolutions this new year – one of them was to restart this blog. Many competing interests made me delinquent, but I am resolved to continue learning! For the first article of this year, we will turn to a long-standing issue in stroke neurology. Does intra-arterial therapy for stroke improve outcomes? Two years ago, I had thought about interventional neurology as a career but was dissuaded by the negative trials. Is intravenous tPA going away in 2015?

Paper: Berkhemer OA, Fransen PSS, Beumer D, et al. "A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke." NEJM (2015); 372(1): 11-20.

Methods: A randomized, multi-center, open label but endpoint blinded trial in Netherlands in which adults admitted within 6 hours of stroke onset with imaging evidence of anterior arterial circulation occlusion were randomized to usual care (including IV tPA) or usual care plus intraarterial therapy (which consisted of mechanical thrombectomy and/or intraarterial thrombolysis). The primary outcome was modified Rankin scale at 90 days (0-6 with 2 or less indicating functional independence).

Results:
Cohort: 500 subjects (233 in intervention arm and 267 in control group) were randomized with mean age of 65 years (range 23 to 96) and 58% males. Median NIH stroke scale was 17 in intervention group and 18 in control. Around 80% in both groups had prestroke modified Rankin scale of 0. IV tPA was used in 87% and 91% of subjects in intervention and control group respectively. Most common imaging finding was M1 segment MCA artery occlusion. Median time from stroke onset to randomization was 204 and 196 minutes respectively in intervention and control groups. In the intervention group, time from stroke onset to groin puncture was 260 minutes.

Clinical Outcome: At 90 days, the median mRS was 3 in intervention group and 4 in control (unadjusted odds ratio of 1.66, 95% CI of 1.21-2.28). Adjusting for variables such as time from stroke to randomization, diabetes, atrial fibrillation, etc., the adjusted odds ration is 1.67 (95% CI: 1.21-2.30). When examining for independence (mRS of 0-2), 32.6% in intervention arm vs 19.1% in control group had mRS of 0-2 at 90 days (OR of 2.16, 95% CI 1.39 to 3.38).

Radiological Outcome: No intracranial occlusion was present in 75.4% in intervention group and 32.9% in control group. Final infarct volume was 49 mL in intervention group and 79 mL in control group.

Adverse Effects: No overall difference in serious adverse effects. However, embolization into new territory occurred in 8.6% of interventions, new dissection from manipulation in 1.7%, and vessel perforation in 0.9%.

Discussion:The trial shows that addition of intraarterial therapy to conventional IV tPA may have clinical benefit. This trial is in contrast to prior ones which did not show a benefit. Two reasons (among many) are that for part of the trial, the procedure was only offered within the context of the trial resulting in inclusion of many patients. In the US, many who are likely to benefit get the procedure anyway and are not included. Secondly, all the patients in this trial unlike previous ones had known arterial occlusion by imaging prior to randomization. While the results are encouraging, this new trial could also be the one lucky one showing benefit among many failed trials. Another major deficit was that the patients were not blinded and may have been biased while reporting! We will likely need follow-up corroborative trials elsewhere prior to accepting this therapy.

Lipoprotein (a) Value

Motivation: Lipoprotein (a) inspires strong emotions among doctors.  Some like it as a risk factor while others see it as a waste of money.  But, when controlled for conventional lipid markers, is it indicative for additional risk for cardiovascular disease?  For background, lipoprotein (a) is a low density LDL-like particle synthesized by the liver which is found in the intima of arteries and presumably promotes atherosclerosis.

Paper: The Emerging Risk Factors Collaboration. "Lipoprotein (a) Concentration and the Risk of Coronary Heart Disease, Stroke, and Nonvascular Mortality."   JAMA (2009); 302: 412-423.

Methods: Meta-analysis of long-term prospective studies that recorded Lipoprotein (a) (Lp(a)) and vascular morbidity.

Results:
Studies: 36 prospective studies met inclusion criteria.  In the analysis, 126 634 participants were included for 1.3 million person-year of follow-up with 22 076 vascular disease outcomes or death.  Mean age at entry was 57 years with 48% women.  Ethnicity was 47% European and 50% North American.

Lipoprotein (a): At baseline, the overall population Lp (a) was 12.6 mg/dL.  Blacks had 119% (95% CI: 84 to 161) higher Lp(a) concentration compared to whites at baseline.  Women had 12% (CI: 8 to 16) higher Lp (a) than men.

Coronary Heart Disease (CHD): When adjusted for age, sex, systolic blood pressure, smoking, diabetes, and total cholesterol, the relative risk of coronary heart disease for the top third of Lp (a) compared to the bottom third was 1.27 (95% CI: 1.17-1.38).  In the top third of subjects with Lp (a), the rate of CHD was 5.6 (95% CI: 5.4-5.9) per 1000 person years compared to rate of 4.4 (95% CI: 4.2-4.6) per 1000 person years in the bottom third.

Ischemic Stroke: When adjusted for usual risk factors, the relative risk (RR) for ischemic stroke was 1.10 (95% CI: 1.02-1.18) per 3.5 fold higher than usual Lp (a) levels.  The relative risk did not reach significance for unclassified stroke and hemorrhagic stroke.

Non-vascular mortality: Lp (a) levels were not associated with increase in non-vascular mortality.

Discussion: Lipoprotein (a) is very modestly associated with independent risk of coronary heart disease and ischemic stroke.  As stated in the paper, compared to the power of Lp (a), elevated non-HDL cholesterol level is four times more strongly associated with coronary heart disease.  There is no drug that independently targets Lp (a) levels.  Consequently, I do not think that at present, it is worth measuring this modestly predictive marker without clear treatment.  The paper, though, illuminated the variability of Lp (a) across ethnicities (blacks have baseline of 100% greater than whites) and genders.  When interpreting raw values of Lp (a), we have to be careful about using correct gender and ethnicity matched norms, which may not exist in all cases.

Stroke Recovery for How Long

Motivation: So, how long does it take to recover? Even after more than a year of treating patients with acute stroke, I am not sure how to answer this question.  I sometimes put it vaguely as "months."  But, really, after how many months do most post-stroke patients complete their recovery?

Paper: Jorgensen HS, Nakayama H, Raaschou HO, Vive-Larsen J, Stoier M, Olsen TS. "Outcome and time course of recovery in stroke: Part II: Time course of recovery. The copenhagen stroke study." Arch Phys Med Rehabil (1995); 76: 406-412.

Methods: All patients with acute stroke in Copenhagen, Denmark between September, 1991 to 1993 were followed from time of acute admission to end of rehabilitation to six months post-stroke.  Time course of recovery was plotted.

Results:
Cohort: The cohort of stroke survivors consisted of 947 patients (53% female) of mean age 73.3.  The strokes were 93% ischemic and 7% hemorrhagic.  The median time between symptom onset and admission was 16 hours.  After rehabilitation, 19% were placed in nursing homes while 81% were discharged home.

Recovery: When assessed by the Scandinavian Stroke Scale (0-58 points, higher indicating milder deficits), best neurological recovery was reached in 80% by 4.5 weeks (95% CI: 4 to 5 weeks) and in 95% by 11 weeks (95% CI: 10.1 to 11.9 weeks) from stroke onset.  Best ADL function (measured by Barthel Index) was reached in 80% by 6 weeks (95% CI: 5.3 to 6.7 weeks) and in 95% by 12.5 weeks (95% CI: 11.6 to 13.4).

Initial Severe Functional Deficits: Severity of functional deficits were judged by the Barthel Index (scale of 0 to 100 with very severe disability in 0-20 and no disability with score of 100).  In those with very severe initial disability (index of 0-20), best ADL function was reached in 80% of patients within 11 weeks (95% CI: 10-12) and in 95% within 17 weeks (95% CI: 15-19).

Initially Mild Disability: In those with mild disability (Barthel Index 75-95), best ADL function was reached in 80% of patients within 2.5 weeks (95% CI: 2-3) in 95% of patients within 5 weeks (95% CI: 4-6).  

Discussion: In this remarkable study with 100% follow-up of all stroke patients in Copenhagen over two years, the overall message is that 95% will regain their best ADL function in about three months.  The rate of recovery is slower in those with more severe disability and more rapid in those with mild disability.  However, even in those with very severe initial functional deficits, best ADL function was reached in 17 months.  For general counseling purposes, an appropriate summary statement might be that mild strokes take about a month to regain best function while severe strokes take about four to five months to regain best function.  While this study is well done, some cautionary aspects are that (1) acute stroke therapy has changed since  the study, and (2) physical therapy has changed since the early 1990s.  How these aspects change the natural history of stroke disorders is unclear.  Also note that this study also talks about the rate of recovery and not the extent of recovery.

A Plavix a Day Keeps MI Away?

Motivation: Last week, I was trying to coax a patient into taking aspirin every day, and he refused to give way.  He had stomach pain after every dose of aspirin.  To me, it seemed reasonable to refuse aspirin, but then again, I did not want his next stroke on my conscience either.  I wondered if there was a way out or even a better way.  How good is clopidogrel compared to aspirin for prevention of vascular events in high risk populations?

Paper: CAPRIE Steering Committee, "A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)" Lancet (1996); 348: 1329-39.

Methods: Randomised blinded trial of 19,185 adults in USA, Canada, and Europe with symptomatic atherosclerotic peripheral arterial disease, recent MI (within 5 weeks), or recent ischemic stroke (within 6 months).  Patients with bleeding disorders were excluded.  Patients were randomized to clopidogrel 75 mg daily or aspirin 325 mg daily.  Primary outcome was ischemic stroke, MI, or vascular death.  Secondary outcomes included all-cause mortality, intracranial hemorrhage, fatal bleeds, and other clusters of outcomes.  Mean duration of follow-up was 1.91 years.

Results: 
Cohort: Among 19,185 patients, 9,586 were randomized to aspirin while 9,599 were randomized to clopidogrel.  Mean age of cohort was 62.5 years, and the cohort was 72% male and 95% white.  Baseline characteristics of the patients in terms of comorbidities were evenly balanced.  Prior to end of study, 21.3% in clopidogrel group and 21.1% in aspirin group discontinued drug.  Most common cause for stopping was adverse drug effect.

Primary Outcome: For the primary outcome of ischemic stroke, MI, or vascular death, the average event rate per patient year was 5.32% in clopidogrel group and 5.83% in aspirin, yielding a relative risk reduction of 8.7% (95% CI 0.3-16.5%, p = 0.043), in favor of clopidogrel.

Secondary Outcome: For the pre-defined secondary outcome measures of vascular death, death from any cause, or cluster of ischemic/hemorrhagic stroke, MI, and death, there was no difference between aspirin and clopidogrel.

Post-Hoc Analysis: In post-hoc subgroup analysis, patients with peripheral arterial disease benefited the most from clopidogrel over aspirin.  The relative risk reduction for clopidogrel over aspirin for primary outcome was 23.8% (CI: 8.9 to 36.2), p = 0.0028.  For patients with MI or stroke, the effect of clopidogrel over aspirin was non-significant.

Adverse Effects: Frequency of rash was higher in clopidogrel over aspirin whereas GI bleed was more frequent in aspirin users.

Discussion: For secondary prevention of vascular events, clopidogrel is at least as good as aspirin.  What was surprising in the post-hoc analysis was the apparent benefit of clopidogrel over aspirin in patients with PAD but not in post-MI and post-stroke patients.  I think that this finding is a note of caution that atherosclerosis in all vascular territories is not equivalent, and benefit of a drug in a type of vascular disease does not necessarily generalize.  The trial was generally well-done, but the 21% rate of drug discontinuation in both groups remains a concern and may have masked beneficial effects in intention-to-treat analysis.  In summary, if a patient balks against aspirin for secondary prevention, daily clopidogrel is an equivalent option and may even be better if patient has PAD.