Exhibit 4.6

AMENDMENT NO. 1 TO WARRANT

TO

PURCHASE STOCK

THIS
AMENDMENT NO. 1 TO WARRANT TO PURCHASE STOCK (this Amendment) is entered into as of the 19thday of February 2009, by and between
ARCA biopharma, Inc., a Delaware corporation (f/k/a Nuvelo, Inc.) and SVB Financial Group.

Recitals

A. The Holder was previously issued a Warrant to Purchase Stock dated as of August 19, 2008 (the Warrant). Capitalized terms used in this
Amendment, but not otherwise defined in this Amendment, shall have the meanings assigned to them in the Warrant.

B. Dawn Acquisition Sub, Inc., a Delaware
corporation and wholly-owned subsidiary of ARCA biopharma, Inc., a Delaware corporation (f/k/a Nuvelo, Inc.), was merged with and into ARCA biopharma Colorado, Inc., a Delaware corporation (f/k/a ARCA biopharma, Inc.) (the
Merger).

C. The Holder and ARCA biopharma, Inc., a Delaware corporation (f/k/a Nuvelo, Inc.) desire to amend the Warrant to reflect the
closing of the Merger, the exchange of the common stock of the Company (as defined below) for the common stock of ARCA biopharma Colorado, Inc., a Delaware corporation (f/k/a ARCA biopharma, Inc.) and assumption of the Warrant as required by
Section 1.6.2(d) of the Warrant in connection with the closing of the Merger.

Amendments

1. The Warrant Price shall be $19.48 per share, subject to adjustment after the date of this Amendment in accordance with the terms of the Warrant.

2. The Number of Shares shall be 6,679, subject to adjustment after the date of this Amendment in accordance with the terms of the Warrant.

3. The Class of Stock shall be the common stock, $0.001 par value per share, of the Company.

4. The Company shall be ARCA biopharma, Inc., a Delaware corporation (f/k/a Nuvelo, Inc.).

5. Except for revisions
expressly set forth in this Amendment, the parties hereby ratify and confirm the terms of the Warrant in their entirety.



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IN WITNESS WHEREOF, the undersigned have executed this Amendment to be effective as of the date first set
forth above.



|                     |  |                                                                                    |  |                     |        |             |                     |                  
|-------------------- |  | ---------------------------------------------------------------------------------- |  | ------------------- | ------ | ----------- | ------------------- | -----------------
|Company:             |  |                                                                                    |  | Holder:            
|                     |  |                                                                                   
|ARCA BIOPHARMA, INC. |  |                                                                                    |  | SVB FINANCIAL GROUP
|                     |  |                                                                                    |  |                    
|By:                  |  | /s/ Christopher D. Ozeroff                                                         |  |                     |        | By:         |                     | /s/ Norman Cutler
|                     |  | Christopher D. Ozeroff, Executive Vice of Business Development and General Counsel |  |                     |        | Print Name: |                     | Norman Cutler    
|                     |  |                                                                                    |  |                     | Title: |             | Derivatives Manager