Clinical profile of stroke in 900 patients with hypertrophic cardiomyopathy

HCM

In each patient, the diagnosis of HCM was based on the two-dimensional echocardiographic identification of a hypertrophied and nondilated LV (wall thickness ≥15 mm in adults, or the equivalent, relative to body surface area, in children) (21)in the absence of another cardiac or systemic disease capable of producing a comparable magnitude of LV hypertrophy (19). Portions of these databases have been utilized in other clinical studies (16–18).

Prevalence

In 843 (94%) of the 900 study patients, the clinical history excluded events consistent with stroke or systemic thromboembolization. Of the other 57 patients, 6 were diagnosed with stroke of hemorrhagic origin or due to a brain tumor.

The remaining 51 patients (6%) experienced one or more cerebrovascular or other peripheral vascular event involving organs other than the CNS (Fig. 1); 38 patients (75%) had a single event, but 13 patients (25%) had multiple occurrences (up to 7) (Table 2). The incidence of these events was 0.8%/year, 0.3% in those ≤40 years old and 1.9% in those >60 years (Table 2).

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Figure 1

Profile of stroke and other peripheral vascular events among 900 patients with hypertrophic cardiomyopathy (HCM). AF = atrial fibrillation; CNS = central nervous system.

AF and left atrial dimension

Of the 900 patients, 708 were in sinus rhythm, and only 6 of these patients experienced events throughout follow-up (0.8% cumulative incidence). By comparison, the 192 patients with paroxysmal or chronic AF had a 23% cumulative incidence of vascular events, or 2.5%/year (Table 2).

Atrial fibrillation was documented in 45 (88%) of the 51 patients with vascular events, either as one or more paroxysmal episode (n = 17) or chronic AF (n = 28); these events were most common in patients with chronic AF (28% vs. 20% for paroxysmal AF). Atrial fibrillation was five times more common in patients with stroke and other peripheral vascular events than in those without (88% vs. 17%; p < 0.001).

In the 51 patients with events, left atrial size was 38 to 72 mm and was normal (≤40 mm) in only 4 patients (8%), including 2 patients with AF. Left atrial dimension was significantly greater in patients with events than in those without (p < 0.001) (Table 1; Fig. 3).

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Figure 3

Comparison of selected clinical features of hypertrophic cardiomyopathy (HCM) in patients with (n = 51) or without (n = 849) stroke and other peripheral vascular events, based on univariate analysis. AF = atrial fibrillation; LA = left atrial.

Variables associated with increased risk of vascular events

Univariate analysis of the relationship between vascular events (stroke or peripheral arterial embolizations at non-CNS sites) and several clinical variables at the initial evaluation is shown in Table 2. There were statistically significant relationships for advanced NYHA functional classes III and IV (p < 0.005), outflow obstruction (p < 0.05), left atrial size (p < 0.005), a history of AF (p < 0.0001) and older age (p < 0.005). In the Cox multivariate regression model, only paroxysmal or chronic AF, severe symptoms at study entry (NYHA functional classes III and IV) and older age at the time of the clinical event proved to be independently related to stroke and other peripheral vascular events (Table 2).

Preventive treatment

Of the 190 patients with a history of chronic or paroxysmal AF, 82 patients received long-term anticoagulation with warfarin. The cumulative incidence of stroke and peripheral arterial embolizations among non-anticoagulated patients with AF was twice that of patients with AF who received warfarin (33 [31%] of 108 patients vs. 15 [18%] 82 patients; p < 0.05).

Of the 51 study patients who experienced confirmed events, 15 patients (29%) had received warfarin on a daily basis and in standard doses, due to a history of AF. Of these 15 patients, 6 patients were known to have international normalized ratios maintained within or near the target therapeutic range of 2 to 3 before their event (i.e., 1.8 to 2.5), whereas in 9 patients, regulation of warfarin administration appeared to be inadequate or was uncertain.

A major hemorrhagic complication as a consequence of anticoagulation occurred in one patient, a 70-year-old man who died of cerebral hemorrhage. Other cardioactive medications administered to patients with events included beta-blockers (n = 23), verapamil (n = 25) and amiodarone (n = 23).

Complications of HCM

Acute vascular events, including stroke and peripheral arterial embolizations, are not sufficiently appreciated as important and occasionally devastating consequences of the natural history of HCM. The frequency with which these complications occur as part of HCM, as well as their clinical determinants, has not yet been systematically characterized. Access to the present consecutive community-based and regional HCM population of 900 patients, relatively unselected and free of tertiary-center referral bias, afforded us the unique opportunity to establish a credible estimate of the prevalence and incidence of stroke and other peripheral vascular events in HCM, as well as the clinical features associated with these disease complications. Indeed, our unusually large study group is particularly well suited for the characterization of uncommon clinical events in a relatively uncommon disease such as HCM (18,24). This would not have been accessible using smaller cohorts, or a purely prospective study design (given the particularly long follow-up period required), nor as relevant if assessed in highly selected tertiary-center patient cohorts less representative of the overall HCM population (15,25).

Prevalence and demographic data

Our data show that these complications are not particularly rare in HCM and may have an important clinical impact on many patients, particularly those >50 years. Over the seven-year follow-up period, stroke and peripheral vascular events occurred in >5% of the patients, and >70% of these events were in patients >50 years of age, in contrast to other adverse consequences of HCM, such as sudden death, which has a predilection for the young (1,3,4). Furthermore, in almost 40% of those patients with vascular events, the consequences were devastating, in terms of disability or death, and 25% had multiple events. Indeed, the incidence and impact of stroke in our HCM cohort appear to far exceed that reported in the general population of comparable age groups (23,26).

Role of AF

The present data also suggest that AF (paroxysmal or chronic), a common arrhythmia in HCM (16,17), is a major determinant of stroke and other peripheral vascular events (26,27). Approximately 90% of our patients with such events had experienced AF (incidence of 2.5%/year), although there appears to be little risk of stroke in the absence of AF (<1%/year). This should be a source of reassurance for the large proportion of patients with HCM in sinus rhythm (including those with an enlarged left atrium), who do not require warfarin. Although all AF episodes tabulated in this data analysis were documented by electrocardiography, we cannot exclude the possibility that those patients with vascular events, but no history of AF (∼10%), may have experienced asymptomatic episodes of this arrhythmia. Therefore, patients with HCM and AF represent a vulnerable subset in which >25% developed events of proven or probable embolic etiology. This strong association between AF and the risk of stroke and other peripheral vascular events exceeds that previously reported in HCM (6,7), as well as in other cardiovascular conditions (23,26–28).

The segment of the HCM cohort with advanced age (>50 years old) was most vulnerable to stroke and other peripheral vascular events, and this risk progressed with age, probably due largely to the more frequent occurrence of AF in older patients. However, an important exception is that subset of patients (i.e., ∼25%) in whom such clinical events occurred before 50 years of age, and in patients as young as age 29. Hence, stroke in HCM does not occur exclusively in older patients, and the possibility of potentially catastrophic cerebral infarcts should be considered in adult patients with HCM of almost any age, particularly in the presence of chronic or paroxysmal AF.

Anticoagulation

Anticoagulation with warfarin has proved highly effective in reducing the incidence of ischemic stroke in patients with AF in conditions other than HCM, particularly in those >60 years (9–14). Our data provide substantiation for this effective prevention of stroke, by showing that prophylactic warfarin treatment was associated with a marked reduction of these ominous and profound complications of HCM. Therefore, we believe that it is warranted to consider such therapy in patients with HCM and chronic AF or one or more paroxysmal episode, after considering the small possibility of hemorrhagic complications and also the necessity for close long-term follow-up and patient compliance. Indeed, because patients with HCM are almost always identified beforea stroke occurs, time is still available for effective prevention of these ominous clinical events.

Our study also raises some important considerations regarding anticoagulant therapy. Warfarin administration for the prevention of cardioembolism did not appear to be absolutely protective, possibly due to inadequate patient compliance or suboptimal drug administration, or to marked degrees of blood stagnation in patients in the end-stage phase (22). Approximately 10% of patients with stroke (who were taking warfarin at the time of their event) were judged to have achieved satisfactory anticoagulant regulation in the optimal therapeutic range, and therefore appear to represent true treatment breakthroughs. It should also be noted that an important proportion of our patients with AF were not on anticoagulant therapy, because their events occurred before the efficacy of warfarin had been established (9,13).

Study limitations

The present investigation was necessarily retrospective, given the uncommon occurrence of HCM in the general population and the relative infrequency of stroke and other peripheral vascular events as complications of HCM. Furthermore, because of acknowledged difficulties in definitively discerning cardioembolic from other stroke subtypes in individual patients, we elected to prudently present our data without making a distinction between embolic and nonembolic stroke. However, in the vast majority of patients in our study cohort judged to have stroke (39 of 44 patients; 88%), these events occurred in the presence of a high-risk source of cardiac emboli, such as AF, and thus are most likely to be cardioembolic in origin according to standard criteria (29). Finally, we believe that the substantial size of the study group (the largest series reported to date for HCM), as well as the long follow-up period, confers substantial power to our data and largely compensates for the retrospective design of the study and the possible uncertainty regarding the etiologic diagnosis of stroke.